Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds

ABSTRACT

The present invention provides methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds, as well as methods of treating, preventing or ameliorating symptoms associated with such diseases. Specific examples of autoimmune diseases that can be treated or prevented with the compounds include rheumatoid arthritis and/or its associated symptoms, systemic lups erythematosis and/or its associated symptoms and multiple sclerosis and/or its associated symptoms.

1. CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 11/539,101,Oct. 5, 2006, which is a continuation of 10/631,029, filed Jul. 29,2003, now U.S. Pat. No. 7,517,886, which claims benefit under 35 U.S.C.§119(e) to application Ser. No. 60/399,673 filed Jul. 29, 2002; Ser. No.60/443,949 filed Jan. 31, 2003 and Ser. No. 60/452,339 filed Mar. 6,2003 all of which are hereby incorporated by reference in thereentirety.

2. FIELD OF THE INVENTION

The present invention relates generally to 2,4-pyrimidinediaminecompounds, pharmaceutical compositions comprising the compounds,intermediates and synthetic methods of making the compounds and methodsof using the compounds and compositions in a variety of contexts, suchas in the treatment or prevention of autoimmune diseases and/or thesymptoms associated therewith.

3. BACKGROUND OF THE INVENTION

Crosslinking of Fc receptors, such as the high affinity receptor for IgE(FcεRI) and/or the high affinity receptor for IgG (FcγRI) activates asignaling cascade in mast, basophil and other immune cells that resultsin the release of chemical mediators responsible for numerous adverseevents. For example, such crosslinking leads to the release of preformedmediators of Type I (immediate) anaphylactic hypersensitivity reactions,such as histamine, from storage sites in granules via degranulation. Italso leads to the synthesis and release of other mediators, includingleukotrienes, prostaglandins and platelet-activating factors (PAFs),that play important roles in inflammatory reactions. Additionalmediators that are synthesized and released upon crosslinking Fcreceptors include cytokines and nitric oxide.

The signaling cascade(s) activated by crosslinking Fc receptors such asFcεRI and/or FcγRI comprises an array of cellular proteins. Among themost important intracellular signal propagators are the tyrosinekinases. And, an important tyrosine kinase involved in the signaltransduction pathways associated with crosslinking the FcεRI and/orFcγRI receptors, as well as other signal transduction cascades, is Sykkinase (see Valent et al., 2002, Intl. J. Hematol. 75(4):257-362 forreview).

As the mediators released as a result of FcεRI and FcγRI receptorcross-linking are responsible for, or play important roles in, themanifestation of numerous adverse events, the availability of compoundscapable of inhibiting the signaling cascade(s) responsible for theirrelease would be highly desireable. Moreover, owing to the critical rolethat Syk kinase plays these and other receptor signaling cascade(s), theavailability of compounds capable of inhibiting Syk kinase would also behighly desirable.

4. SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel2,4-pyrimidinediamine compounds that, as will be discussed in moredetail below, have myriad biological activities. The compounds generallycomprise a 2,4-pyrimidinediamine “core” having the following structureand numbering convention:

The compounds of the invention are substituted at the C2 nitrogen (N2)to form a secondary amine and are optionally further substituted at oneor more of the following positions: the C4 nitrogen (N4), the C5position and/or the C6 position. When substituted at N4, the substituentforms a secondary amine. The substituent at N2, as well as the optionalsubstituents at the other positions, may range broadly in character andphysico-chemical properties. For example, the substituent(s) may be abranched, straight-chained or cyclic alkyl, a branched, straight-chainedor cyclic heteroalkyl, a mono- or polycyclic aryl a mono- or polycyclicheteroaryl or combinations of these groups. These substituent groups maybe further substituted, as will be described in more detail below.

The N2 and/or N4 substituents may be attached directly to theirrespective nitrogen atoms, or they may be spaced away from theirrespective nitrogen atoms via linkers, which may be the same ordifferent. The nature of the linkers can vary widely, and can includevirtually any combination of atoms or groups useful for spacing onemolecular moiety from another. For example, the linker may be an acyclichydrocarbon bridge (e.g, a saturated or unsaturated alkyleno such asmethano, ethano, etheno, propano, prop[1]eno, butano, but[l]eno,but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclichydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, and the like),a simple acyclic heteroatomic or heteroalkyldiyl bridge (e.g., —O—, —S—,—S—O—, —NH—, —PH—, —C(O)—, —C(O)NH—, —S(O)—, —S(O)₂—, —S(O)NH—,—S(O)₂NH—, —O—CH₂—, —CH₂—O—CH₂—, —O—CH═CH—CH₂—, and the like),monocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano, pyridino,thiopheno, piperidino, piperazino, pyrazidino, pyrrolidino, and thelike) or combinations of such bridges.

The substituents at the N2, N4, C5 and/or C6 positions, as well as theoptional linkers, may be further substituted with one or more of thesame or different substituent groups. The nature of these substituentgroups may vary broadly. Non-limiting examples of suitable substituentgroups include branched, straight-chain or cyclic alkyls, mono- orpolycyclic aryls, branched, straight-chain or cyclic heteroalkyls, mono-or polycyclic heteroaryls, halos, branched, straight-chain or cyclichaloalkyls, hydroxyls, oxos, thioxos, branched, straight-chain or cyclicalkoxys, branched, straight-chain or cyclic haloalkoxys,trifluoromethoxys, mono- or polycyclic aryloxys, mono- or polycyclicheteroaryloxys, ethers, alcohols, sulfides, thioethers, sulfanyls(thiols), imines, azos, azides, amines (primary, secondary andtertiary), nitriles (any isomer), cyanates (any isomer), thiocyanates(any isomer), nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonicacids, sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones,carboxylic acids, esters, amides, amidines, formadines, amino acids,acetylenes, carbamates, lactones, lactams, glucosides, gluconurides,sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamicesters, etc., and combinations of these groups. Substituent groupsbearing reactive functionalities may be protected or unprotected, as iswell-known in the art.

In one illustrative embodiment, the 2,4-pyrimidinediamine compounds ofthe invention are compounds according to structural formula (1):

including salts, hydrates, solvates and N-oxides thereof, wherein:

L¹ and L² are each, independently of one another, selected from thegroup consisting of a direct bond and a linker;

R² is selected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-Cl5) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups;

R⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyloptionally substituted with one or more of the same or different R⁸groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups, cyclohexyl optionally substituted withone or more of the same or different R⁸ groups, 3-8 memberedcycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups,

(C5-C15) aryl optionally substituted with one or more of the same ordifferent R⁸ groups, phenyl optionally substituted with one or more ofthe same or different R⁸ groups and 5-15 membered heteroaryl optionallysubstituted with one or more of the same or different R⁸ groups;

R⁵ is selected from the group consisting of R⁶, (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C1-C4)alkanyl optionally substituted with one or more of the same or differentR⁸ groups, (C2-C4) alkenyl optionally substituted with one or more ofthe same or different R⁸ groups and (C2-C4) alkynyl optionallysubstituted with one or more of the same or different R⁸ groups;

each R⁶ is independently selected from the group consisting of hydrogen,an electronegative group, —OR^(d), —SR^(d), (C1-C3) haloalkyloxy,(C1-C3) perhaloalkyloxy, —NR^(c)R^(c), halogen, (C1-C3) haloalkyl,(C1-C3) perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CN, —NC, —OCN, —SCN, —NO,—NO₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c);—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d),—OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and—[NHC(NH)]_(n)NR^(c)R^(c), (C5-C10) aryl optionally substituted with oneor more of the same or different R⁸ groups, phenyl optionallysubstituted with one or more of the same or different R⁸ groups,(C6-C16) arylalkyl optionally substituted with one or more of the sameor different R⁸ groups, 5-10 membered heteroaryl optionally substitutedwith one or more of the same or different R⁸ groups and 6-16 memberedheteroarylalkyl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁸ is selected from the group consisting of R^(a), R^(b), R^(a)substituted with one or more of the same or different R^(a) or R^(b),—OR^(a) substituted with one or more of the same or different R^(a) orR^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b),—O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),—C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)R^(b), —S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);

each R^(a) is independently selected from the group consisting ofhydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl,piperazinyl, homopiperazinyl, piperidinyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl;

each R^(b) is a suitable group independently selected from the groupconsisting of αO, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d),—OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c),—C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d),—OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c),—[NHC(O)]_(n)R^(d), —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d),—[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c),—[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and—[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);

each R^(c) is independently a protecting group or R^(a), or,alternatively, each R^(c) is taken together with the nitrogen atom towhich it is bonded to form a 5 to 8-membered cycloheteroalkyl orheteroaryl which may optionally include one or more of the same ordifferent additional heteroatoms and which may optionally be substitutedwith one or more of the same or different R^(a) or suitable R^(b)groups;

each R^(d) is independently a protecting group or R^(a);

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

In another aspect, the present invention provides prodrugs of the2,4-pyrimidinediamine compounds. Such prodrugs may be active in theirprodrug form, or may be inactive until converted under physiological orother conditions of use to an active drug form. In the prodrugs of theinvention, one or more functional groups of the 2,4-pyrimidinediaminecompounds are included in promoieties that cleave from the moleculeunder the conditions of use, typically by way of hydrolysis, enzymaticcleavage or some other cleavage mechanism, to yield the functionalgroups. For example, primary or secondary amino groups may be includedin an amide promoiety that cleaves under conditions of use to generatethe primary or secondary amino group. Thus, the prodrugs of theinvention include special types of protecting groups, termed“progroups,” masking one or more functional groups of the2,4-pyrimidinediamine compounds that cleave under the conditions of useto yield an active 2,4-pyrimidinediamine drug compound. Functionalgroups within the 2,4-pyrimidinediamine compounds that may be maskedwith progroups for inclusion in a promoiety include, but arc not limitedto, amines (primary and secondary), hydroxyls, sulfanyls (thiols),carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates,etc. Myriad progroups suitable for masking such functional groups toyield promoieties that are cleavable under the desired conditions of useare known in the art. All of these progroups, alone or in combinations,may be included in the prodrugs of the invention. Specific examples ofpromoieties that yield primary or secondary amine groups that can beincluded in the prodrugs of the invention include, but are not limitedto amides, carbamates, imines, ureas, phosphenyls, phosphoryls andsulfenyls. Specific examples of promoieties that yield sulfanyl groupsthat can be included in the prodrugs of the invention include, but arenot limited to, thioethers, for example S-methyl derivatives (monothio,dithio, oxythio, aminothio acetals), silyl thioethers, thioesters,thiocarbonates, thiocarbamates, asymmetrical disulfides, etc. Specificexamples of promoieties that cleave to yield hydroxyl groups that can beincluded in the prodrugs of the invention include, but are not limitedto, sulfonates, esters and carbonates. Specific examples of promoietiesthat yield carboxyl groups that can be included in the prodrugs of theinvention included, but are not limited to, esters (including silylesters, oxamic acid esters and thioesters), amides and hydrazides.

In one illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (I) in which the protectinggroup of R^(c) and R^(d) is a progroup.

Replacing the hydrogens attached to N2 and N4 in the2,4-pyrimidinediamines of structural formula (I) with substituentsadversely affects the activity of the compounds. However, as will beappreciated by skilled artisans, these nitrogens may be included inpromoieties that, under conditions of use, cleave to yield2,4-pyrimidinediamines according to structural formula (I). Thus, inanother illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (II):

including salts, hydrates, solvates and N-oxides thereof, wherein:

R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined for structuralformula (I); and

R^(2b) and R^(4b) are each, independently of one another, a progroup.

In another aspect, the present invention provides compositionscomprising one or more compounds and/or prodrugs of the invention and anappropriate carrier, excipient or diluent. The exact nature of thecarrier, excipient or diluent will depend upon the desired use for thecomposition, and may range from being suitable or acceptable forveterinary uses to being suitable or acceptable for human use.

In still another aspect, the present invention provides intermediatesuseful for synthesizing the 2,4-pyrimidinediamine compounds and prodrugsof the invention. In one embodiment, the intermediates are4-pyrimidineamines according to structural formula (III):

including salts, hydrates, solvates and N-oxides thereof, wherein R⁴,R⁵, R⁶ and L² are as previously defined for structural formula (I); LGis a leaving group such as, for example, —S(O)₂Me, —SMe or halo (e.g.,F, Cl, Br, I); and R^(4c) is hydrogen or a progroup.

In another embodiment, the intermediates are 2-pyrimidineaminesaccording to structural formula (IV):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁵, R⁶ and L¹ are as previously defined for structural formula (I); LGis a leaving group, such as, for example, —S(O)₂Me, —SMe or halo (e.g.,F, Cl, Br, I) and R^(2c) is hydrogen or a progroup.

In yet another embodiment, the intermediates are 4-amino- or4-hydroxy-2-pyrimidineamines according to structural formula (V):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁵, R⁶ and L¹ are as previously defined for structural formula (I), R⁷is an amino or hydroxyl group and R^(2c) is hydrogen or a progroup.

In another embodiment, the intermediates are N4-substituted cytosinesaccording to structural formula (VI):

including salts, hydrates, solvates and N-oxides thereof, wherein R⁴,R⁵, R⁶ and L² are as previously defined for structural formula (I) andR^(4c) is hydrogen or a progroup.

In yet another aspect, the present invention provides methods ofsynthesizing the 2,4-pyrimidinediamine compounds and prodrugs of theinvention. In one embodiment, the method involves reacting a4-pyrimidineamine according to structural formula (III) with an amine ofthe formula HR^(2c)N-L¹-R², where L¹, R² and R² are as previouslydefined for structural formula (IV) to yield a 2,4-pyrimidinediamineaccording to structural formula (I) or a prodrug according to structuralformula (II).

In another embodiment, the method involves reacting a 2-pyrimidineamineaccording to structural formula (IV) with an amine of the formulaR⁴-L²-NHR^(4c) where L⁴, R⁴ and R^(4c) are as previously defined forstructural formula (III) to yield a 2,4-pyrimidinediamine according tostructural formula (I) or a prodrug according to structural formula(II).

In yet another embodiment, the method involves reacting a4-amino-2-pyrimidineamine according to structural formula (V) (in whichR⁷ is an amino group) with an amine of the formula R⁴-L²-NHR^(4c), whereL², R⁴ and R^(4c) are as defined for structural formula (III), to yielda 2,4-pyrimidinediamine according to structural formula (I) or a prodrugaccording to structural formula (II). Alternatively, the4-amino-2-pyrimidineamine may be reacted with a compound of the formulaR⁴-L²-LG, where R⁴ and L² are as previously defined for structuralformula (1) and LG is a leaving group.

In still another embodiment, the method involves halogenating a4-hydroxy-2-pyrimidineamine according to structural formula (V) (R⁷ is ahydroxyl group) to yield a 2-pyrimidineamine according to structuralformula (IV) and reacting this pyrimidineamine with an appropriateamine, as described above.

In yet another embodiment, the method involves halogenating anN4-substituted cytosine according to structural formula (VI) to yield a4-pyrimidineamine according to structural formula (III) and reactingthis pyrimidineamine with an appropriate amine, as described above.

The 2,4-pyrimidinediamine compounds of the invention are potentinhibitors of degranulation of immune cells, such as mast, basophil,neutrophil and/or eosinophil cells. Thus, in still another aspect, thepresent invention provides methods of regulating, and in particularinhibiting, degranulation of such cells. The method generally involvescontacting a cell that degranulates with an amount of a2,4-pyrimidinediamine compound or prodrug of the invention, or anacceptable salt, hydrate, solvate, N-oxide and/or composition thereof,effective to regulate or inhibit degranulation of the cell. The methodmay be practiced in in vitro contexts or in in vivo contexts as atherapeutic approach towards the treatment or prevention of diseasescharacterized by, caused by or associated with cellular degranulation.

While not intending to be bound by any theory of operation, biochemicaldata confirm that the 2,4-pyrimidinediamine compounds exert theirdegranulation inhibitory effect, at least in part, by blocking orinhibiting the signal transduction cascade(s) initiated by crosslinkingof the high affinity Fc receptors for IgE (“FcεRI”) and/or IgG(“FcγRI”). Indeed, the 2,4-pyrimidinediamine compounds are potentinhibitors of both FcεRI-mediated and FcγRI-mediated degranulation. As aconsequence, the 2,4-pyrimidine compounds may be used to inhibit theseFc receptor signalling cascades in any cell type expressing such FcεRIand/or FcγRI receptors including but not limited to macrophages, mast,basophil, neutrophil and/or eosinophil cells.

The methods also permit the regulation of, and in particular theinhibition of, downstream processes that result as a consequence ofactivating such Fc receptor signaling cascade(s). Such downstreamprocesses include, but are not limited to, FcεRI-mediated and/orFcγRI-mediated degranulation, cytokine production and/or the productionand/or release of lipid mediators such as leukotrienes andprostaglandins. The method generally involves contacting a cellexpressing an Fc receptor, such as one of the cell types discussedabove, with an amount of a 2,4-pyrimidinediamine compound or prodrug ofthe invention, or an acceptable salt, hydrate, solvent, N-oxide and/orcomposition thereof, effective to regulate or inhibit the Fc receptorsignaling cascade and/or a downstream process effected by the activationof this signaling cascade. The method may be practiced in in vitrocontexts or in in vivo contexts as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by orassociated with the Fc receptor signaling cascade, such as diseaseseffected by the release of granule specific chemical mediators upondegranulation, the release and/or synthesis of cytokines and/or therelease and/or synthesis of lipid mediators such as leukotrienes andprostaglandins.

In yet another aspect, the present invention provides methods oftreating and/or preventing diseases characterized by, caused by orassociated with the release of chemical mediators as a consequence ofactivating Fc receptor signaling cascades, such as FcεRI and/orFcγRI-signaling cascades. The methods may be practiced in animals inveterinary contexts or in humans. The methods generally involveadministering to an animal subject or human an amount of a2,4-pyrimidinediamine compound or prodrug of the invention, or anacceptable salt, hydrate, solvate, N-oxide and/or composition thereof,effective to treat or prevent the disease. As discussed previously,activation of the FcεRI or FcγRI receptor signaling cascade in certainimmune cells leads to the release and/or synthesis of a variety ofchemical substances that are pharmacological mediators of a wide varietyof diseases. Any of these diseases may be treated or prevented accordingto the methods of the invention.

For example, in mast cells and basophil cells, activation of the FcεRIor FcγRI signaling cascade leads to the immediate (i.e., within 1-3 min.of receptor activation) release of preformed mediators of atopic and/orType I hypersensitivity reactions (e.g., histamine, proteases such astryptase, etc.) via the degranulation process. Such atopic or Type Ihypersensitivity reactions include, but are not limited to, anaphylacticreactions to environmental and other allergens (e.g., pollens, insectand/or animal venoms, foods, drugs, contrast dyes, etc.), anaphylactoidreactions, hay fever, allergic conjunctivitis, allergic rhinitis,allergic asthma, atopic dermatitis, eczema, urticaria, mucosaldisorders, tissue disorders and certain gastrointestinal disorders.

The immediate release of the preformed mediators via degranulation isfollowed by the release and/or synthesis of a variety of other chemicalmediators, including, among other things, platelet activating factor(PAF), prostaglandins and leukotrienes (e.g., LTC4) and the de novosynthesis and release of cytokines such as TNFα, IL-4, IL-5, IL-6,IL-13, etc. The first of these two processes occurs approximately 3-30min. following receptor activation; the latter approximately 30 min. −7hrs. following receptor activation. These “late stage” mediators arethought to be in part responsible for the chronic symptoms of theabove-listed atopic and Type I hypersensitivity reactions, and inaddition are chemical mediators of inflammation and inflammatorydiseases (e.g., osteoarthritis, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, idiopathic inflammatory bowel disease,irritable bowel syndrome, spastic colon, etc.), low grade scarring(e.g., scleroderma, increased fibrosis, keloids, post-surgical scars,pulmonary fibrosis, vascular spasms, migraine, reperfusion injury andpost myocardial infarction), and sicca complex or syndrome. All of thesediseases may be treated or prevented according to the methods of theinvention.

Additional diseases which can be treated or prevented according to themethods of the invention include diseases associated with basophil celland/or mast cell pathology. Examples of such diseases include, but arenot limited to, diseases of the skin such as scleroderma, cardiacdiseases such as post myocardial infarction, pulmonary diseases such aspulmonary muscle changes or remodeling and chronic obstructive pulmonarydisease (COPD) and diseases of the gut such as inflammatory bowelsyndrome (spastic colon).

The 2,4-pyrimidinediamine compounds of the invention are also potentinhibitors of the tyrosine kinase Syk kinase. Thus, in still anotheraspect, the present invention provides methods of regulating, and inparticular inhibiting, Syk kinase activity. The method generallyinvolves contacting a Syk kinase or a cell comprising a Syk kinase withan amount of a 2,4-pyrimidinediamine compound or prodrug of theinvention, or an acceptable salt, hydrate, solvate, N-oxide and/orcomposition thereof, effective to regulate or inhibit Syk kinaseactivity. In one embodiment, the Syk kinase is an isolated orrecombinant Syk kinase. In another embodiment, the Syk kinase is anendogenous or recombinant Syk kinase expressed by a cell, for example amast cell or a basophil cell. The method may be practiced in in vitrocontexts or in in vivo contexts as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by orassociated with Syk kinase activity.

While not intending to be bound by any particular theory of operation,it is believed that the 2,4-pyrimdinediamine compounds of the inventioninhibit cellular degranulation and/or the release of other chemicalmediators primarily by inhibiting Syk kinase that gets activated throughthe gamma chain homodimer of FcεRI (see, e.g., FIG. 2). This gamma chainhomodimer is shared by other Fc receptors, including FcγRI, FcγRIII andFcαRI. For all of these receptors, intracellular signal transduction ismediated by the common gamma chain homodimer. Binding and aggregation ofthose receptors results in the recruitment and activation of tyrosinekinases such as Syk kinase. As a consequence of these common signalingactivities, the 2,4-pyrimidinediamine compounds described herein may beused to regulate, and in particular inhibit, the signaling cascades ofFc receptors having this gamma chain homodimer, such as FcεRI, FcγRI,FcγRIII and FcαRI, as well as the cellular responses elicited throughthese receptors.

Syk kinase is known to play a critical role in other signaling cascades.For example, Syk kinase is an effector of B-cell receptor (BCR)signaling (Turner et al., 2000, Immunology Today 21:148-154) and is anessential component of integrin beta(1), beta(2) and beta(3) signalingin neutrophils (Mocsai et al., 2002, Immunity 16:547-558). As the2,4-pyrimidinediamine compounds described herein are potent inhibitorsof Syk kinase, they can be used to regulate, and in particular inhibit,any signaling cascade where Syk plays a role, such as, fore example, theFc receptor, BCR and integrin signaling cascades, as well as thecellular responses elicited through these signaling cascades. Theparticular cellular response regulated or inhibited will depend, inpart, on the specific cell type and receptor signaling cascade, as iswell known in the art. Non-limiting examples of cellular responses thatmay be regulated or inhibited with the 2,4-pyrimidinediamine compoundsinclude a respiratory burst, cellular adhesion, cellular degranulation,cell spreading, cell migration, phagocytosis (e.g., in macrophages),calcium ion flux (e.g., in mast, basophil, neutrophil, eosinophil andB-cells), platelet aggregation, and cell maturation (e.g., in B-cells).

Thus, in another aspect, the present invention provides methods ofregulating, and in particular inhibiting, signal transduction cascadesin which Syk plays a role. The method generally involves contacting aSyk-dependent receptor or a cell expressing a Syk-dependent receptorwith an amount of a 2,4-pyrimidinediamine compound or prodrug of theinvention, or an acceptable salt, hydrate, solvate, N-oxide and/orcomposition thereof, effective to regulate or inhibit the signaltransduction cascade. The methods may also be used to regulate, and inparticular inhibit, downstream processes or cellular responses elicitedby activation of the particular Syk-dependent signal transductioncascade. The methods may be practiced to regulate any signaltransduction cascade where Syk is not known or later discovered to playa role. The methods may be practiced in in vitro contexts or in in vivocontexts as a therapeutic approach towards the treatment or preventionof diseases characterized by, caused by or associated with activation ofthe Syk-dependent signal transduction cascade. Non-limited examples ofsuch diseases include those previously discussed.

Cellular and animal data also confirm that the 2,4-pyrimidinediaminecompounds of the invention may also be used to treat or preventautoimmune diseases and/or symptoms of such diseases. The methodsgenerally involve administering to a subject suffering from anautoimmune disease or at risk of developing an autoimmune disease anamount of a 2,4-pyrimidinediamine method or prodrug of the invention, oran acceptable salt, N-oxide, hydrate, solvate or composition thereof,effective to treat or prevent the autoimmune disease and/or itsassociated symptoms. Autoimmune diseases that can be treated orprevented with the 2,4-pyrimidinediamine compounds include thosediseases that are commonly associated with nonanaphylactichypersensitivity reactions (Type II, Type III and/or Type IVhypersensitivity reactions) and/or those diseases that are mediated, atleast in part, by activation of the FcγR signaling cascade in monocytecells. Such autoimmune disease include, but are not limited to, thoseautoimmune diseases that are frequently designated as single organ orsingle cell-type autoimmune disorders and those autoimmune disease thatare frequently designated as involving systemic autoimmune disorder.Non-limiting examples of diseases frequently designated as single organor single cell-type autoimmune disorders include: Hashimoto'sthyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritisof pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, autoimmune thrombocytopenia, sympatheticophthalmia, myasthenia gravis, Graves' disease, primary biliarycirrhosis, chronic aggressive hepatitis, ulcerative colitis andmembranous glomerulopathy. Non-limiting examples of diseases oftendesignated as involving systemic autoimmune disorder include: systemiclupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter'ssyndrome, polymyositis-dermatomyositis, systemic sclerosis,polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.

5. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a cartoon illustrating allergen-induced production ofIgE and consequent release of preformed and other chemical mediatorsfrom mast cells;

FIG. 2 provides a cartoon illustrating the FcεR1 signal transductioncascade leading to degranulation of mast and/or basophil cells;

FIG. 3 provides a cartoon illustrating the putative points of action ofcompounds that selectively inhibit upstream FcεRI-mediated degranulationand compounds that inhibit both FcεRI-mediated and ionomycin-induceddegranulation;

FIG. 4 provides graphs illustrating the effects of certain2,4-pyrimidinediamine compounds, DMSO (control) and ionomycin on Ca²⁺flux in CHMC cells;

FIG. 5 provides graphs illustrating the immediacy of the inhibitoryactivity of compounds R921218 and R926495;

FIG. 6 provides a graph illustrating the effect of washout on theinhibitory activity of compounds R921218 and R921302;

FIG. 7 provides data showing that varying concentrations of compoundsR921218 (A) and R921219 (B) inhibit phosporylation of various proteinsdownstream of Syk kinase in the IgE receptor signal transduction cascadein activated BMMC cells;

FIG. 8 provides data showing dose responsive inhibition of Syk kinasephosphorylation of an endogenous substrate (LAT) and a peptide substratein the presence of increasing concentrations of compounds R921218 (X),R921219 (Y) and R921304 (Z);

FIG. 9 provides data showing that the inhibition of Syk kinase bycompound R921219 is ATP competitive;

FIG. 10 provides data showing that varying concentrations of compoundsR921219 (A) and 8218218 (B) inhibit phosphorylation of proteinsdownstream of Syk kinase, but not LYN kinase, in the FcεRI signaltransduction cascade in activated CHMC cells; also shown is inhibitionof phosphorylation of proteins downstream of LYN kinase but not Sykkinase, in the presence of a known LYN kinase inhibitor (PP2);

FIGS. 11A-D provide data showing inhibition of phosphorylation ofproteins downstream of Syk kinase in the FcεRI signal transductioncascade in BMMC cells;

FIG. 12 is a graph illustrating the efficacy of compound R921302 in amouse model of collagen antibody-induced arthritis (“CAIA”);

FIG. 13 is a graph illustrating the efficacy of compound R921302 in theCAIA model as compared to other agents and control agents;

FIG. 14 is a graph illustrating the efficacy of compound R921302 in arat model of collagen-induced arthritis (“CIA”);

FIG. 15 is a graph illustrating the efficacy of compound R921302 ininhibiting experimental autoimmune encephalomyelitis (“EAE”) in mice, aclinical model for multiple sclerosis; and

FIG. 16 is a graph illustrating the efficacy compound R921302 on SJLmice treated on the starting day of immunization with 150 μg PLP139-151/200 μg MTB (CFA).

6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

6.1 Definitions

As used herein, the following terms are intended to have the followingmeanings:

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated branched, straight-chain or cyclic monovalenthydrocarbon radical having the stated number of carbon atoms (i.e.,C1-C6 means one to six carbon atoms) that is derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkeneor alkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl,”“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C1-C6) alkyl.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-y1 (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like. Inpreferred embodiments, the alkanyl groups are (C1-C6) alkanyl.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon double bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkene. The group may be in eitherthe cis or trans conformation about the double bond(s). Typical alkenylgroups include, but are not limited to, ethenyl; propenyls such asprop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like. In preferred embodiments, the alkenyl group is (C2-C6)alkenyl.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon triple bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In preferredembodiments, the alkynyl group is (C2-C6) alkynyl.

“Alkyldiyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic divalenthydrocarbon group having the stated number of carbon atoms (i.e., C1-C6means from one to six carbon atoms) derived by the removal of onehydrogen atom from each of two different carbon atoms of a parentalkane, alkene or alkyne, or by the removal of two hydrogen atoms from asingle carbon atom of a parent alkane, alkene or alkyne. The twomonovalent radical centers or each valency of the divalent radicalcenter can form bonds with the same or different atoms. Typicalalkyldiyl groups include, but are not limited to, methandiyl; ethyldiylssuch as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl;propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl,propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl,prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl,prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as,butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl,cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; andthe like. Where specific levels of saturation are intended, thenomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Whereit is specifically intended that the two valencies are on the samecarbon atom, the nomenclature “alkylidene” is used. In preferredembodiments, the alkyldiyl group is (C1-C6) alkyldiyl. Also preferredare saturated acyclic alkanyldiyl groups in which the radical centersare at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl(ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and thelike (also referred to as alkylenos, defined infra).

“Alkyleno” by itself or as part of another substituent refers to astraight-chain saturated or unsaturated alkyldiyl group having twoterminal monovalent radical centers derived by the removal of onehydrogen atom from each of the two terminal carbon atoms ofstraight-chain parent alkane, alkene or alkyne. The locant of a doublebond or triple bond, if present, in a particular alkyleno is indicatedin square brackets. Typical alkyleno groups include, but are not limitedto, methano; ethylenos such as ethano, etheno, ethyno; propylenos suchas propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenossuch as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno,but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature alkano, alkeno and/or alkynois used. In preferred embodiments, the alkyleno group is (C1-C6) or(C1-C3) alkyleno. Also preferred are straight-chain saturated alkanogroups, e.g., methano, ethano, propano, butano, and the like.

“Heteroalkyl,” Heteroalkanyl,” Heteroalkenyl,” Heteroalkynyl,”Heteroalkyldiyl” and “Heteroalkyleno” by themselves or as part ofanother substituent refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyland alkyleno groups, respectively, in which one or more of the carbonatoms are each independently replaced with the same or differentheteratoms or heteroatomic groups. Typical heteroatoms and/orheteroatomic groups which can replace the carbon atoms include, but arenot limited to, —O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)₂—,—S(O)NR′—, —S(O)₂NR′—, and the like, including combinations thereof,where each R′ is independently hydrogen or (C1-C6) alkyl.

“Cycloalkyl” and “Heterocycloalkyl” by themselves or as part of anothersubstituent refer to cyclic versions of “alkyl” and “heteroalkyl”groups, respectively. For heteroalkyl groups, a heteroatom can occupythe position that is attached to the remainder of the molecule. Typicalcycloalkyl groups include, but are not limited to, cyclopropyl;cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such ascyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl andcyclohexenyl; and the like. Typical heterocycloalkyl groups include, butare not limited to, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, etc.), piperidinyl (e.g., piperidin-1-yl,piperidin-2-yl, etc.), morpholinyl (e.g., morpholin-3-yl,morpholin-4-yl, etc.), piperazinyl (e.g., piperazin-1-yl,piperazin-2-yl, etc.), and the like.

“Acyclic Heteroatomic Bridge” refers to a divalent bridge in which thebackbone atoms are exclusively heteroatoms and/or heteroatomic groups.Typical acyclic heteroatomic bridges include, but are not limited to,—O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)₂—, —S(O)NR′—, —S(O)₂NR′—,and the like, including combinations thereof, where each R′ isindependently hydrogen or (C1-C6) alkyl.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene,tetrahydronaphthalene, etc. Typical parent aromatic ring systemsinclude, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and thelike, as well as the various hydro isomers thereof.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon group having the stated number of carbonatoms (i.e. , C5-C 15 means from 5 to 15 carbon atoms) derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like, as well as thevarious hydro isomers thereof. In preferred embodiments, the aryl groupis (C5-C15) aryl, with (C5-C10) being even more preferred. Particularlypreferred aryls are cyclopentadienyl, phenyl and naphthyl.

“Arylaryl” by itself or as part of another substituent refers to amonovalent hydrocarbon group derived by the removal of one hydrogen atomfrom a single carbon atom of a ring system in which two or moreidentical or non-identical parent aromatic ring systems are joineddirectly together by a single bond, where the number of such direct ringjunctions is one less than the number of parent aromatic ring systemsinvolved. Typical arylaryl groups include, but are not limited to,biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, biphenyl-naphthyl, andthe like. Where the number of carbon atoms in an arylaryl group arespecified, the numbers refer to the carbon atoms comprising each parentaromatic ring. For example, (C5-C15) arylaryl is an arylaryl group inwhich each aromatic ring comprises from 5 to 15 carbons, e.g., biphenyl,triphenyl, binaphthyl, phenylnaphthyl, etc. Preferably, each parentaromatic ring system of an arylaryl group is independently a (C5-C15)aromatic, more preferably a (C5-C10) aromatic. Also preferred arearylaryl groups in which all of the parent aromatic ring systems areidentical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

“Biaryl” by itself or as part of another substituent refers to anarylaryl group having two identical parent aromatic systems joineddirectly together by a single bond. Typical biaryl groups include, butare not limited to, biphenyl, binaphthyl, bianthracyl, and the like.Preferably, the aromatic ring systems are (C5-C15) aromatic rings, morepreferably (C5-C10) aromatic rings. A particularly preferred biarylgroup is biphenyl.

“Arylalkyl” by itself or as part of another substituent refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylakenyl and/orarylalkynyl is used. In preferred embodiments, the arylalkyl group is(C6-C21) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C1-C6) and the aryl moiety is (C5-C15). Inparticularly preferred embodiments the arylalkyl group is (C6-C13),e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is(C1-C3) and the aryl moiety is (C5-C10).

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms are each independently replacedwith the same or different heteroatoms or heteroatomic groups. Typicalheteroatoms or heteroatomic groups to replace the carbon atoms include,but are not limited to, N, NH, P, O, S, S(O), S(O)₂, Si, etc.Specifically included within the definition of “parent heteroaromaticring systems” are fused ring systems in which one or more of the ringsare aromatic and one or more of the rings are saturated or unsaturated,such as, for example, benzodioxan, benzofuran, chromane, chromene,indole, indoline, xanthene, etc. Also included in the definition of“parent heteroaromatic ring system” are those recognized rings thatinclude common substituents, such as, for example, benzopyrone and1-methyl-1,2,3,4-tetrazole. Specifically excluded from the definition of“parent heteroaromatic ring system” are benzene rings fused to cyclicpolyalkylene glycols such as cyclic polyethylene glycols. Typical parentheteroaromatic ring systems include, but are not limited to, acridine,benzimidazole, benzisoxazole, benzodioxan, benzodioxole, benzofuran,benzopyrone, benzothiadiazole, benzothiazole, benzotriazole,benzoxaxine, benzoxazole, benzoxazoline, carbazole, β-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

“Heteroaryl” by itself or as part of another substituent refers to amonovalent heteroaromatic group having the stated number of ring atoms(e.g., “5-14 membered” means from 5 to 14 ring atoms) derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, benzimidazole,benzisoxazole, benzodioxan, benzodiaxole, benzofuran, benzopyrone,benzothiadiazole, benzothiazole, benzotriazole, benzoxazine,benzoxazole, benzoxazoline, carbazole, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike, as well as the various hydro isomers thereof. In preferredembodiments, the heteroaryl group is a 5-14 membered heteroaryl, with5-10 membered heteroaryl being particularly preferred.

“Heteroaryl-Heteroaryl” by itself or as part of another substituentrefers to a monovalent heteroaromatic group derived by the removal ofone hydrogen atom from a single atom of a ring system in which two ormore identical or non-identical parent heteroaromatic ring systems arejoined directly together by a single bond, where the number of suchdirect ring junctions is one less than the number of parentheteroaromatic ring systems involved. Typical heteroaryl-heteroarylgroups include, but are not limited to, bipyridyl, tripyridyl,pyridylpurinyl, bipurinyl, etc. Where the number of atoms are specified,the numbers refer to the number of atoms comprising each parentheteroaromatic ring systems. For example, 5-15 memberedheteroaryl-heteroaryl is a heteroaryl-heteroaryl group in which eachparent heteroaromatic ring system comprises from 5 to 15 atoms, e.g.,bipyridyl, tripuridyl, etc. Preferably, each parent heteroaromatic ringsystem is independently a 5-15 membered heteroaromatic, more preferablya 5-10 membered heteroaromatic. Also preferred are heteroaryl-heteroarylgroups in which all of the parent heteroaromatic ring systems areidentical.

“Biheteroaryl” by itself or as part of another substituent refers to aheteroaryl-heteroaryl group having two identical parent heteroaromaticring systems joined directly together by a single bond. Typicalbiheteroaryl groups include, but are not limited to, bipyridyl,bipurinyl, biquinolinyl, and the like. Preferably, the heteroaromaticring systems are 5-15 membered heteroaromatic rings, more preferably5-10 membered heteroaromatic rings.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In preferred embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In particularlypreferred embodiments, the heteroarylalkyl is a 6-13 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

“Halogen” or “Halo” by themselves or as part of another substituent,unless otherwise stated, refer to fluoro, chloro, bromo and iodo.

“Haloalkyl” by itself or as part of another substituent refers to analkyl group in which one or more of the hydrogen atoms is replaced witha halogen. Thus, the term “haloalkyl” is meant to includemonohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.For example, the expression “(C1-C2) haloalkyl” includes fluoromethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl,1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.

The above-defined groups may include prefixes and/or suffixes that arecommonly used in the art to create additional well-recognizedsubstituent groups. As examples, “alkyloxy” or “alkoxy” refers to agroup of the formula —OR″, “alkylamine” refers to a group of the formula—NHR″ and “dialkylamine” refers to a group of the formula −NR″R″, whereeach R″ is independently an alkyl. As another example, “haloalkoxy” or“haloalkyloxy” refers to a group of the formula —OR′″, where R′″ is ahaloalkyl.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative aminoprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated or alkylated such as benzyl and trityl ethers, as wellas alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g.,TMS or TIPPS groups) and allyl ethers.

“Prodrug” refers to a derivative of an active 2,4-pyrimidinediaminecompound (drug) that requires a transformation under the conditions ofuse, such as within the body, to release the active2,4-pyrimidinediamine drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. Prodrugs are typically obtained by masking a functional group inthe 2,4-pyrimidinediamine drug believed to be in part required foractivity with a progroup (defined below) to form a promoiety whichundergoes a transformation, such as cleavage, under the specifiedconditions of use to release the functional group, and hence the active2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceedspontaneously, such as by way of a hydrolysis reaction, or it may becatalyzed or induced by another agent, such as by an enzyme, by light,by acid or base, or by a change of or exposure to a physical orenvironmental parameter, such as a change of temperature. The agent maybe endogenous to the conditions of use, such as an enzyme present in thecells to which the prodrug is administered or the acidic conditions ofthe stomach, or it may be supplied exogenously.

A wide variety of progroups, as well as the resultant promoieties,suitable for masking functional groups in the active2,4-pyrimidinediamines compounds to yield prodrugs are well-known in theart. For example, a hydroxyl functional group may be masked as asulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivoto provide the hydroxyl group. An amino functional group may be maskedas an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenylpromoiety, which may be hydrolyzed in vivo to provide the amino group. Acarboxyl group may be masked as an ester (including silyl esters andthioesters), amide or hydrazide promoiety, which may be hydrolyzed invivo to provide the carboxyl group. Other specific examples of suitableprogroups and their respective promoieties will be apparent to those ofskill in the art.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active 2,4-pyrimidinediamine drug to form apromoiety, converts the drug into a prodrug. Progroups are typicallyattached to the functional group of the drug via bonds that arecleavable under specified conditions of use. Thus, a progroup is thatportion of a promoiety that cleaves to release the functional groupunder the specified conditions of use. As a specific example, an amidepromoiety of the formula —NH—C(O)CH₃ comprises the progroup —C(O)CH₃.

“Fc Receptor” refers to a member of the family of cell surface moleculesthat binds the Fc portion (containing the specific constant region) ofan immunoglobulin. Each Fc receptor binds immunoglobulins of a specifictype. For example the Fcα receptor (“FcαR”) binds IgA, the FcεR bindsIgE and the FcγR binds IgG.

The FcαR family includes the polymeric Ig receptor involved inepithelial transport of IgA/IgM, the mycloid specific receptor RcαRI(also called CD89), the Fcα/μR and at least two alternative IgAreceptors (for a recent review see Monteiro & van de Winkel, 2003, AnnuRev. Immunol, advanced e-publication. The FcαRI is expressed onneutrophils, eosinophils, moncytes/macrophages, dendritic cells andkupfer cells. The FcαRI includes one alpha chain and the FcR gammahomodimer that bears an activation motif (ITAM) in the cytoplasmicdomain and phosphorylates Syk kinase.

The FcεR family includes two types, designated FcεRI and FcεRII (alsoknown as CD23). FcεRI is a high affinity receptor (binds IgE with anaffinity of about 10¹⁰M⁻¹) found on mast, basophil and eosinophil cellsthat anchors monomeric IgE to the cell surface. The FcεRI possesses onealpha chain, one beta chain and the gamma chain homodimer discussedabove. The FcεRII is a low affinity receptor expressed on mononuclearphagocytes, B lymphocytes, eosinophils and platelets. The FcεRIIcomprises a single polypeptide chain and does not include the gammachain homodimer.

The FcγR family includes three types, designated FcγRI (also known asCD64), FcγRII (also known as CD32) and FcγRIII (also known as CD16).FcγRI is a high affinity receptor (binds IgG1 with an affinity of10⁸M⁻¹) found on mast, basophil, mononuclear, neutrophil, eosinophil,deudritic and phagocyte cells that anchors nomomeric IgG to the cellsurface. The FcγRI includes one alpha chain and the gamma chain dimershared by FcαRI and FcεRI.

The FcγRII is a low affinity receptor expressed on neutrophils,monocytes, eosinophils, platelets and B lymphocytes. The FcγRII includesone alpha chain, and does not include the gamma chain homodimerdiscussed above.

The FcγRIII is a low affinity (bindes IgG1 with an affinity of 5×10⁵M⁻¹)expressed on NK, eosinophil, macrophage, neutrophil and mast cells. Itcomprises one alpha chain and the gamma homodimer shared by FcαRI, FcεRIand FcγRI.

Skilled artisans will recognize that the subunit structure and bindingproperties of these various Fc receptors, cell types expressing them,are not completely characterized. The above discussion merely reflectsthe current state-of-the-art regarding these receptors (see, e.g.,Immunobiology: The Immune System in Health & Disease, 5^(th) Edition,Janeway et al., Eds, 2001, ISBN 0-8153-3642-x, FIG. 9.30 at pp. 371),and is not intended to be limiting with respect to the myriad receptorsignaling cascades that can be regulated with the compounds describedherein.

“Fc Receptor-Mediated Degranulation” or “Fc Receptor-InducedDegranulation” refers to degranulation that proceeds via an Fc receptorsignal transduction cascade initiated by crosslinking of an Fc receptor.

“IgE-Induced Degranulation” or “FcεRI-Mediated Degranulation” refers todegranulation that proceeds via the IgE receptor signal transductioncascade initiated by crosslinking of FcεR1-bound IgE. The crosslinkingmay be induced by an IgE-specific allergen or other multivalent bindingagent, such as an anti-IgE antibody. Referring to FIG. 2, in mast and/orbasophil cells, the FcεRI signaling cascade leading to degranulation maybe broken into two stages: upstream and downstream. The upstream stageincludes all of the processes that occur prior to calcium ionmobilization (illustrated as “Ca²⁺” in FIG. 2; see also FIG. 3). Thedownstream stage includes calcium ion mobilization and all processesdownstream thereof Compounds that inhibit FcεRI-mediated degranulationmay act at any point along the FcεRI-mediated signal transductioncascade. Compounds that selectively inhibit upstream FcεRI-mediateddegranulation act to inhibit that portion of the FcεRI signaling cascadeupstream of the point at which calcium ion mobilization is induced. Incell-based assays, compounds that selectively inhibit upstreamFcεRI-mediated degranulation inhibit degranulation of cells such as mastor basophil cells that are activated or stimulated with an IgE-specificallergen or binding agent (such as an anti-IgE antibody) but do notappreciably inhibit degranulation of cells that are activated orstimulated with degranulating agents that bypass the FcεRI signalingpathway, such as, for example the calcium ionophores ionomycin andA23187.

“IgG-Induced Degranulation” or “FcγRI-Mediated Degranulation” refers todegranulation that proceeds via the FcγRI signal transduction cascadeinitiated by crosslinking of FcγRI-bound IgG. The crosslinking may beinduced by an IgG-specific allergen or another multivalent bindingagent, such as an anti-IgG or fragment antibody. Like the FcεRIsignaling cascade, in mast and basophil cells the FcγRI signalingcascade also leads to degranulation which may be broken into the sametwo stages: upstream and downstream. Similar to FcεRI-mediateddegranulation, compounds that selectively inhibit upstreamFcγRI-mediated degranulation act upstream of the point at which calciumion mobilization is induced. In cell-based assays, compounds thatselectively inhibit upstream FcγRI-mediated degranulation inhibitdegranulation of cells such as mast or basophil cells that are activatedor stimulated with an IgG-specific allergen or binding agent (such as ananti-IgG antibody or fragment) but do not appreciably inhibitdegranulation of cells that are activated or stimulated withdegranulating agents that bypass the FcγRI signaling pathway, such as,for example the calcium ionophores ionomycin and A23187.

“Ionophore-Induced Degranulation” or “Ionophore-Mediated Degranulation”refers to degranulation of a cell, such as a mast or basophil cell, thatoccurs upon exposure to a calcium ionophore such as, for example,ionomycin or A23187.

“Syk Kinsase” refers to the well-known 72 kDa non-receptor (cytoplasmic)spleen protein tyrosine kinase expressed in B-cells and otherhematopoetic cells. Syk kinase includes two consensus Src-homology 2(SH2) domains in tandem that bind to phosphorylated immunoreceptortyrosine-based activation motifs (“ITAMs”), a “linker” domain and acatalytic domain (for a review of the structure and function of Sykkinase see Sada et al., 2001, J. Biochem. (Tokyo) 130:177-186); see alsoTurner et al., 2000, Immunology Today 21:148-154). Syk kinase has beenextensively studied as an effector of B-cell receptor (BCR) signaling(Turner et al., 2000, supra). Syk kinase is also critical for tyrosinephosphorylation of multiple proteins which regulate important pathwaysleading from immunoreceptors, such as Ca²⁺ mobilization andmitogen-activated protein kinase (MAPK) cascades (see, e.g., FIG. 2) anddegranulation. Syk kinase also plays a critical role in integrinsignaling in neutrophils (see, e.g., Mocsai et al. 2002, Immunity16:547-558).

As used herein, Syk kinase includes kinases from any species of animal,including but not limited to, homosapiens, simian, bovine, porcine,rodent, etc., recognized as belonging to the Syk family. Specificallyincluded are isoforms, splice variants, allelic variants, mutants, bothnaturally occuring and man-made. The amino acid sequences of such Sykkinases are well known and available from GENBANK. Specific examples ofmRNAs encoding different isoforms of human Syk kinase can be found atGENBANK accession no. gi|21361552|ref|NM_(—)003177.2|,gi|496899|emb|Z29630.1|HSSYKPTK[496899] andgi|15030258|gb|BC011399.1|BC011399[15030258], which are incorporatedherein by reference.

Skilled artisans will appreciate that tyrosine kinases belonging toother families may have active sites or binding pockets that are similarin three-dimensional structure to that of Syk. As a consequence of thisstructural similarity, such kinases, referred to herein as “Syk mimics,”are expected to catalyze phosphorylation of substrates phosphorylated bySyk. Thus, it will be appreciated that such Syk mimics, signaltransduction cascades in which such Syk mimics play a role andbiological responses effected by such Syk mimics and Syk mimic-dependentsignaling cascades may be regulated, and in particular inhibited, withthe 2,4-pyrimidinediamine compounds described herein.

“Syk-Dependent Signaling Cascade” refers to a signal transductioncascade in which Syk kinase plays a role. Non-limiting examples of suchSyk-dependent signaling cascades include the FcαRI, FcεRI, FcγRI,FcγRIII, BCR and integrin signaling cascades.

“Autoimmune Disease” refers to those diseases which are commonlyassociated with the nonanaphylactic hypersensitivity reactions (Type II,Type III and/or Type IV hypersensitivity reactions) that generallyresult as a consequence of the subject's own humoral and/orcell-mediated immune response to one or more immunogenic substances ofendogenous and/or exogenous origin. Such autoimmune diseases aredistinguished from diseases associated with the anaphylactic (Type 1 orIgE-mediated) hypersensitivity reactions.

6.2 The 2,4-Pyrimidinediamine Compounds

The compounds of the invention are generally 2,4-pyrimidinediaminecompounds according to structural formula (I):

including salts, hydrates, solvates and N-oxides thereof, wherein:

L¹ and L² are each, independently of one another, selected from thegroup consisting of a direct bond and a linker;

R² is selected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-C15) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups;

R⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyloptionally substituted with one or more of the same or different R⁸groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups, cyclohexyl optionally substituted withone or more of the same or different R⁸ groups, 3-8 memberedcycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, (C5-C15) aryl optionally substituted with one ormore of the same or different R⁸ groups, phenyl optionally substitutedwith one or more of the same or different R⁸ groups and 5-15 memberedheteroaryl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁵ is selected from the group consisting of R⁶, (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C1-C4)alkanyl optionally substituted with one or more of the same or differentR⁸ groups, (C2-C4) alkenyl optionally substituted with one or more ofthe same or different R⁸ groups and (C2-C4) alkynyl optionallysubstituted with one or more of the same or different R⁸ groups;

each R⁶ is independently selected from the group consisting of hydrogen,an electronegative group, —OR^(d), —SR^(d), (C1-C3) haloalkyloxy,(C1-C3) perhaloalkyloxy, —NR^(c)R^(c), halogen, (C1-C3) haloalkyl,(C1-C3) perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CN, —NC, —OCN, —SCN, —NO,—NO₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d),—OS(O)NR^(c)R^(c), —OC(O)_(n)NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d),—OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and—[NHC(NH)]_(n)NR^(c)R^(c), (C5-C10) aryl optionally substituted with oneor more of the same or different R⁸ groups, (C6-C16) arylalkyloptionally substituted with one or more of the same or different R⁸groups, 5-10 membered heteroaryl optionally substituted with one or moreof the same or different R⁸ groups and 6-16 membered heteroarylalkyloptionally substituted with one or more of the same or different R⁸groups;

R⁸ is selected from the group consisting of R^(a), R^(b), R^(a)substituted with one or more of the same or different R^(a) or R^(b),—OR_(a) substituted with one or more of the same or different R^(a) orR^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b),—C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);

each R^(a) is independently selected from the group consisting ofhydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl,piperazinyl, homopiperazinyl, piperidinyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl;

each R^(b) is a suitable group independently selected from the groupconsisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d),—OS(O)₂R^(d), —OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d),—C(O)OR^(d), —C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c),—C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d),—OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c),—[NHC(O)]_(n)R^(d), —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d),—[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NRR^(c),—[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and—[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);

each R^(c) is independently R^(a), or, alternatively, each R^(c) istaken together with the nitrogen atom to which it is bonded to form a 5to 8-membered cycloheteroalkyl or heteroaryl which may optionallyinclude one or more of the same or different additional heteroatoms andwhich is optionally substituted with one or more of the same ordifferent R^(a) or suitable R^(b) groups;

each R^(d) is independently R^(a);

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

In the compounds of structural formula (I), L¹ and L² represent,independently of one another, a direct bond or a linker. Thus, as willbe appreciated by skilled artisans, the substituents R² and/or R⁴ may bebonded either directly to their respective nitrogen atoms or,alternatively, spaced away from their respective nitrogen atoms by wayof a linker. The identity of the linker is not critical and typicalsuitable linkers include, but are not limited to, (C1-C6) alkyldiyls,(C1-C6) alkanos and (C1-C6) heteroalkyldiyls, each of which may beoptionally substituted with one or more of the same or different R⁸groups, where R⁸ is as previously defined for structural formula (I). Ina specific embodiment, L¹ and L² are each, independently of one another,selected from the group consisting of a direct bond, (C1-C3) alkyldiyloptionally substituted with one or more of the same or different R^(a),suitable R^(b) or R⁹ groups and 1-3 membered heteroalkyldiyl optionallysubstituted with one or more of the same or different R^(a), suitableR^(b) or R⁹ groups, wherein R⁹ is selected from the group consisting of(C1-C3) alkyl, —OR^(a), —C(O)OR^(a), (C5-C10) aryl optionallysubstituted with on or more of the same or different halogens, phenyloptionally substituted with one or more of the same or differenthalogens, 5-10 membered heteroaryl optionally substituted with one ormore of the same or different halogens and 6 membered heteroaryloptionally substituted with one or more of the same or differenthalogens; and R^(a) and R^(b) are as previously defined for structuralformula (I). Specific R⁹ groups that may be used to substitute L¹ and L²include —OR^(a), —C(O)OR^(a), phenyl, halophenyl and 4-halophenyl,wherein R^(a) is as previously defined for structural formula (I).

In another specific embodiment, L¹ and L² are each, independently of oneanother, selected from the group consisting of methano, ethano andpropano, each of which may be optionally monosubstituted with an R⁹group, where R⁹ is as previously defined above.

In all of the above embodiments, specific R^(a) groups that may beincluded in R⁹ groups are selected from the group consisting ofhydrogen, (C1-C6) alkyl, phenyl and benzyl.

In still another specific embodiment, L¹ and L² are each a direct bondsuch that the 2,4-pyrimidinediamine compounds of the invention arecompounds according to structural formula (Ia):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁴, R⁵ and R⁶ are as previously defined for structural formula (I).Additional specific embodiments of the 2,4-pyrimidinediamine compoundsof the invention are described below.

In a first embodiment of the compounds of structural formulae (I) and(Ia), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined for theirrespective structures (I) and (Ia), with the proviso that R² is not3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6) alkoxyphenyl or

where R²¹, R²² and R²³ are as defined for R¹, R² and R³, respectively ofU.S. Pat. No. 6,235,746, the disclosure of which is incorporated byreference. In a specific embodiment of this first embodiment, R²¹ ishydrogen, halo, straight-chain or branched (C1-C6) alkyl optionallysubstituted with one or more of the same or different R²⁵ groups,hydroxyl, (C1-C6) alkoxy optionally substituted with one or more of thesame or different phenyl or R²⁵ groups, thiol (—SH), (C1-C6) alkylthiooptionally substituted with one or more of the same or different phenylor R²⁵ groups, amino (—NH₂), —NHR²⁶ or —NR²⁶R²⁶; R²² and R²³ are each,independently of one another, a (C1-C6) straight-chain or branched alkyloptionally substituted with one or more of the same or different R²⁵groups; R²⁵ is selected from the group consisting of halo, hydroxyl,(C1-C6) alkoxy, thiol, (C1-C6) alkylthio, (C1-C6) alkylamino and (C1-C6)dialkylamino; and each R²⁶ is independently a (C1-C6) alkyl optionallysubstituted with one or more of the same or different phenyl or R²⁵groups or a —C(O)R²⁷, where R²⁷ is a (C1-C6) alkyl optionallysubstituted with one or more of the same or different phenyl or R²⁵groups.

In another specific embodiment of this first embodiment, R²¹ is methoxyoptionally substituted with one or more of the same or different halogroups and/or R²² and R²³ are each, independently of one another, amethyl or ethyl optionally substituted with one or more of the same ordifferent halo groups.

In a second embodiment of the compounds of structural formulae (I) and(Ia), R², R⁴, R⁵ and L² are as previously described for their respectivestructures (I) and (Ia), L¹ is a direct bond and R⁶ is hydrogen, withthe proviso that R² is not 3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6)alkoxyphenyl or

where R²¹, R²² and R²³ are as defined above, in connection with thefirst embodiment.

In a third embodiment, the 2,4-pyrimidinediamine compounds of structuralformulae (I) and (Ia) exclude one or more of the following compounds:

N2,N4-bis(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R070790);

N2,N4-bis(2-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R081166);

N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R088814);

N2,N4-bis(2-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R088815);

N2,N4-bisphenyl-5-fluoro-2,4-pyrimidinediamine (R091880);

N2,N4-bis(3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (R092788);

N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R067962);

N2,N4-bis(2,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067963);

N2,N4-bis(3,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067964);

N2,N4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R0707153);

N2,N4-bis(2,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R070791);

N2,N4-bis(3-bromophenyl)-5-fluoro-2,4-pyrimidinediamine (R008958);

N2,N4-bis(phenyl)-5-fluoro-2,4-pyrimidinediamine;

N2,N4-bis(morpholino)-5-fluoro-2,4-pyrimidinediamine; and

N2,N4-bis[(3-chloro-4-methoxyphenyl)]-5-fluoro-2,4-pyrimidinediamine.

In a fourth embodiment, the compounds of structural formulae (I) and(Ia) exclude compounds according to the following structural formula(Ib):

wherein R²⁴ is 1 (C1-C6) alkyl; and R²¹, R²² and R²³ are as previouslydefined in connection with the first embodiment.

In a fifth embodiment, the compounds of structural formulae (I) and (Ia)exclude the compounds described in Examples 1-141 of U.S. Pat. No.6,235,746, the disclosure of which is incorporated herein by reference.

In a sixth embodiment, the compounds of structural formulae (I) and (Ia)exclude compounds defined by formula (1) or formula 1(a) of this U.S.Pat. No. 6,235,746 (see, e.g., the disclosure at Col. 1, line 48 throughCol. 7, line 49 and Col. 8, lines 9-36, which is incorporated byreference).

In a seventh embodiment, the compounds of structural formulae (I) and(Ia) exclude compounds in which R⁵ is cyano or —C(O)NHR, where R ishydrogen or (C1-C6) alkyl, when R² is a substituted phenyl; R4 is asubstituted or unsubstituted (C1-C6) alkyl, (C₃-C₈) cycloalkyl, 3-8membered cycloheteralkyl or 5-15 membered heteroaryl; and R⁶ ishydrogen.

In an eighth embodiment, the compounds of structural formulae (I) and(Ia) exclude the compounds defined by formulae (I) and (X) of WO02/04429 or any compound disclosed in WO 02/04429, the disclosure ofwhich is incorporated herein by reference.

In a ninth embodiment of the compounds of structural formulae (I) and(Ia), when R⁵ is cyano or —C(O)NHR, where R is hydrogen or (C1-C6)alkyl; and R⁶ is hydrogen, then R² is other than a substituted phenylgroup.

In a tenth embodiment, the compounds of structural formulae (I) and (Ia)exclude compounds in which R² and R⁴ are each independently asubstituted or unsubstituted pyrrole or indole ring which is attached tothe remainder of the molecule via its ring nitrogen atom.

In an eleventh embodiment, the compounds of structural formulae (I) and(Ia) exclude compounds defined by formulae (I) and (IV) of U.S. Pat. No.4,983,608 or any compound disclosed in U.S. Pat. No. 4,983,608, thedisclosure of which is incorporated herein by reference.

Those of skill in the art will appreciate that in the compounds offormulae (I) and (Ia), R² and R⁴ may be the same or different, and mayvary broadly. When R² and/or R⁴ are optionally substituted rings, suchas optionally substituted cycloalkyls, cycloheteroalkyls, aryls andheteroaryls, the ring may be attached to the remainder of the moleculethrough any available carbon or heteroatom. The optional substituentsmay be attached to any available carbon atoms and/or heteroatoms.

In a twelfth embodiment of the compounds of structural formulae (I) and(Ia), R² and/or R⁴ is an optionally substituted phenyl or an optionallysubstituted (C5-C15) aryl, subject to the provisos that (1) when R⁶ ishydrogen, then R² is not 3,4,5-trimethoxyphenyl or 3,4,5-tri (C1-C6)alkoxyphenyl; (2) when R² is a 3,4,5-trisubstituted phenyl, then thesubstituents at the 3- and 4-positions are not simultaneously methoxy or(C1-C6) alkoxy; or (3) when R⁶ is hydrogen and R⁴ is (C1-C6) alkyl,(C3-C₈) cycloalkyl, 3-8 membered cycloheteroalkyl or 5-15 memberedheteroaryl, then R⁵ is other than cyano. Alternatively, R² is subject tothe provisos described in connection with the first or secondembodiments. The optionally substituted aryl or phenyl group may beattached to the remainder of the molecule through any available carbonatom. Specific examples of optionally substituted phenyls includephenyls that are optionally mono-, di- or tri-substituted with the sameor different R⁸ groups, where R⁸ is as previously defined for structuralformula (I) and subject to the above provisos. When the phenyl ismono-substituted, the R⁸ substituent may be positioned at either theortho, meta or para position. When positioned at the ortho, meta or paraposition, R⁸ is preferably selected from the group consisting of (C 1-C10) alkyl, (C1-C10) branched alkyl, —OR^(a) optionally substituted withone or more of the same or different R^(b) groups, —O—C(O)OR^(a),—O—(CH₂)_(m)—C(O)OR^(a), —C(O)OR^(a), —O—(CH₂)_(m)—NR^(c)R^(c),—O—C(O)NR^(c)R^(c), —O—(CH₂)_(m)—C(O)NR^(c)R^(c), —O—C(NH)NR^(c)R^(c),—O—(CH₂)_(m)—C(NH)NR^(c)R^(c) and —NH—(CH₂)_(m)—NR^(c)R^(c), where m,R^(a) and R^(c) are as previously defined for structural formula (I). Inone embodiment of these compounds, —NR^(c)R^(c) is a 5-6 memberedheteroaryl which optionally includes one or more of the same ordifferent additional heteroatoms. Specific examples of such 5-6 memberedheteroaryls include, but are not limited to, oxadiazolyl, triazolyl,thiazolyl, oxazolyl, tetrazolyl and isoxazolyl.

In another embodiment of these compounds, —NR^(c)R^(c) is a 5-6 memberedsaturated cycloheteroalkyl ring which optionally includes one or more ofthe same or different heteroatoms. Specific examples of suchcycloheteroalkyls include, but are not limited to, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl.

In still another embodiment of these compounds, each R^(a) isindependently a (C1-C6) alkyl and/or each —NR^(c)R^(c) is —NHR^(a),where R^(a) is a (C1-C6) alkyl. In one specific embodiment, R⁸ is—O—CH₂—C(O)NHCH₃. In another specific embodiment R⁸ is —OH.

When the phenyl is di-substituted or tri-substituted, the R⁸substituents may be positioned at any combination of positions. Forexample, the R⁸ substituents may be positioned at the 2,3-, 2,4-, 2,5-,2,6-, 3,4-, 3,5-, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6-, 2,5,6- or3,4,5-positions. In one embodiment of compounds including adisubstituted phenyl, the substituents are positioned other than 3,4. Inanother embodiment they are positioned 3,4. In one embodiment ofcompounds including a trisubstituted phenyl, the substituents arepositioned other than 3,4,5 or, alternatively, no two of thesubstituents are positioned 3,4. In another embodiment, the substituentsare positioned 3,4,5.

Specific examples of R⁸ substituents in such di- and trisubstitutedphenyls include the various R⁸ substituents described above inconnection with the ortho, meta and para substituted phenyls.

In another specific embodiment, R⁸ substituents useful for substitutingsuch di-and trisubstituted phenyls include (C1-C6) alkyl, (C1-C6)alkoxy, methoxy, halo, chloro, (C1-C6) perhaloalkyl, —CF₃, (C1-C6)perhaloalkoxy and —OCF₃. In a preferred embodiment, such R⁸ substituentsare positioned 3,4 or 3,5. Specific examples of preferred di-substitutedphenyl rings include 3-chloro-4-methoxy-phenyl,3-methoxy-4-chlorophenyl, 3-chloro-4-trifluoromethoxy-phenyl,3-trifluoromethoxy-4-chloro-phenyl, 3,4-dichloro-phenyl,3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl, with the provisos that: (1)when R⁴ is one of the above-identified phenyls, and R⁵ and R⁶ are eachhydrogen, then R² is not 3,4,5-tri(C1-C6)alkoxyphenyl or3,4,5-trimethoxyphenyl; (2) when R² is 3,4-dimethoxyphenyl and R⁵ and R⁶are each hydrogen, then R4 is not 3-(C1-C6)alkoxyphenyl,3-methoxyphenyl, 3,4-di-(C1-C6) alkoxyphenyl or 3,4-dimethoxyphenyl; (3)when R⁴ is 3-chloro-4-methoxyphenyl and R⁵ is halo or fluoro, andoptionally R⁶ is hydrogen, then R² is not 3-chloro-4-(C1-C6)alkoxyphenylor 3-chloro-4-methoxyphenyl; (4) when R⁴ is 3,4-dichlorophenyl, R⁵ ishydrogen, (C1-C6) alkyl, methyl, halo or chloro and optionally R⁶ ishydrogen, then R² is not a phenyl mono substituted at the para positionwith a (C1-C6) alkoxy group which is optionally substituted with one ormore of the same or different R^(b), —OH or —NR^(c)R^(c) groups, whereR^(b) and R^(c) are as previously described for structural formula (I);and/or (5) R² and/or R⁴ is not 3,4,5-tri(C1-C6)alkoxyphenyl or3,4,5-trimethoxyphenyl, especially when R⁵ and R⁶ are each hydrogen.

In another embodiment of compounds including a trisubstituted phenyl,the trisubstituted phenyl has the formula:

wherein: R³¹ is methyl or (C1-C6) alkyl; R³² is hydrogen, methyl or(C1-C6) alkyl; and R³³ is a halo group.

In a thirteenth embodiment of the compounds of structural formulae (I)and (Ia), R² and/or R⁴ is an optionally substituted heteroaryl. Typicalheteroaryl groups according to this thirteenth embodiment comprise from5 to 15, and more typically from 5 to 11 ring atoms, and include one,two, three or four of the same or different heteratoms or heteroatomicgroups selected from the group consisting of N, NH, 0, S, S(O) andS(O)₂. The optionally substituted heteroaryl may be attached to itsrespective C2 or C4 nitrogen atom or linker L¹ or L² through anyavailable carbon atom or heteroatom, but is typically attached via acarbon atom. The optional substituents may be the same or different, andmay be attached to any available carbon atom or heteroatom. In oneembodiment of these compounds, R⁵ is other than bromo, nitro,trifluoromethyl, cyano or —C(O)NHR, where R is hydrogen or (C1-C6)alkyl. In another embodiment of these compounds, when R² and R⁴ are eacha substituted or unsubstituted pyrrole or indole, then the ring isattached to the remainder of the molecule via a ring carbon atom. Instill another embodiment of compounds including an optionallysubstituted heteroaryl group, the heteroaryl is unsubstituted orsubstituted with from one to four of the same or different R^(s) groups,where R^(R) is as previously defined for structural formula (I).Specific examples of such optionally substituted heteroaryls include,but are not limited to, the following heteroaryl groups:

wherein:

-   -   p is an integer from one to three;    -   each        independently represents a single bond or a double bond;    -   R³⁵ is hydrogen or R⁸, where R⁸ is as previously defined for        structural formula (I);    -   X is selected from the group consisting of CH, N and N—O;    -   each Y is independently selected from the group consisting of O,        S and NH;    -   each Y¹ is independently selected from the group consisting of        O, S, SO, SO₂, SONR³⁶, NH and NR³⁷;    -   each Y² is independently selected from the group consisting of        CH, CH₂, O, S, N, NH and NR³⁷;    -   R³⁶ is hydrogen or alkyl;    -   R³⁷ is selected from the group consisting of hydrogen and a        progroup, preferably hydrogen or a progroup selected from the        group consisting of aryl, arylalkyl, heteroaryl, R^(a),        R^(b)—CR^(a)R^(b)—O—C(O)R⁸, —CR^(a)R^(b)—O—PO(OR⁸)₂,        —CH₂—O—PO(OR⁸)₂, —CH₂—PO(OR⁸)₂, —C(O)—CR^(a)R^(b)—N(CH₃)₂,        —CR^(a)R^(b)—O—C(O)—CR^(a)R^(b)—N(CH₃)₂, —C(O)R⁸, —C(O)CF₃ and        —C(O)—NR⁸—C(O)R⁸;    -   A is selected from the group consisting of O, NH and NR³⁸;    -   R³⁸ is selected from the group consisting of alkyl and aryl;    -   R⁹, R¹⁰, R₁₁ and R¹² are each, independently of one another,        selected from the group consisting of alkyl, alkoxy, halogen,        haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹        and R¹⁰ and/or R¹¹ and R¹² are taken together form a ketal;    -   each Z is selected from the group consisting of hydroxyl,        alkoxy, aryloxy, ester, carbamate and sulfonyl;    -   Q is selected from the group consisting of —OH, OR⁸,        —NR^(c)R^(c), —NHR³⁹—C(O)R⁸, —NHR³⁹—C(O)OR⁸, —NR³⁹—CHR⁴⁰—R^(b),        —NR³⁹—(CH₂)_(m)—R^(b) and —NR³⁹—C(O)—CHR⁴⁰—NR^(c)R^(c);    -   R³⁹ and R⁴⁰ are each, independently of one another, selected        from the group consisting of hydrogen, alkyl, aryl,        alkylaryl;arylalkyl and NHR⁸; and    -   R^(a), R^(b) and R^(c) are as previously defined for structural        formula (I). Preferred R^(b) substitutents for Q are selected        from —C(O)OR⁸, —O—C(O)R⁸, —O—P(O)(OR⁸)₂ and —P(O)(OR)⁸)₂.

In one embodiment of the above-depicted heteroaryls, as well as other5-15 membered heteroaryls according to this embodiment of the invention,each R⁸ is independently selected from the group consisting of R^(d),—NR^(c)R^(c), —(CH₂)_(m)—NR^(c)R^(c), —C(O)NR^(c)R^(c),—(CH₂)_(m)—C(O)NR^(c)R^(c), —C(O)OR^(d), —(CH₂)_(m)—C(O)OR^(d) and—(CH₂)_(m)—OR^(d), where m, R^(c) and R^(d) are as previously definedfor structural formula (I).

In a specific embodiment, R^(d) and/or R^(c) is selected from the groupconsisting of R^(a) and (C3-C8) cycloalkyl optionally substituted withone or more of the same or different hydroxyl, amino or carboxyl groups.

In another embodiment of the above-depicted heteroaryls, each R³⁵ is ahydrogen atom, a (C1-C6) carbon chain, including methyl, ethyl,isopropyl, a cycloalkyl group, including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a

wherein x=1-8,—CH₂CONHMe, —CH₂CH₂NHMe, —CH₂CH₂CONHMe, —CH₂CH₂CH₂NHMe or—CH₂CH₂CH₂OCH₃.

In still another embodiment of the above-depicted heteroaryls, thearomatic ring connectivity is either at the 5 or 6 position. It shouldbe understood that either R² or R⁴ can utilize the heteroaryl groupsdiscussed throughout this specification.

In a fourteenth embodiment of the compounds of structural formulae (I)and (Ia), R² and R⁴ are each, independently of one another, anoptionally substituted phenyl, aryl or heteroaryl, with the provisosthat: (1) when L¹ is a direct bond and R⁶ and optionally R⁵ is hydrogen,then R² is other than 3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-C6)alkoxyphenyl; (2) when L¹ and L² are each a direct bond, R⁶ is hydrogenand R⁵ is halo, then R² and R⁴ are not each simultaneously3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-C6) alkoxyphenyl; (3) when R⁴ is3-methoxyphenyl or 3-(C1-C6) alkoxyphenyl and R² is a3,4,5-trisubstituted phenyl, the substituents positioned at the 3 and 4positions are not both simultaneously methoxy or (C1-C6) alkoxy; (4)when R² is a substituted phenyl and R⁶ is hydrogen, then R⁵ is otherthan cyano or —C(O)NHR, where R is hydrogen or (C1-C6) alkyl; and/or (5)when R² and R⁴ are each independently a substituted or unsubstitutedpyrrole or indole, then the pyrrole or indole is attached to theremainder of the molecule via a ring carbon atom. Alternatively, R² issubject to the provisos described in connection with the first or secondembodiment.

In this fourteenth embodiment of the invention, the R² and R⁴substituents may be the same or different. Specific optionallysubstituted phenyl, aryl and/or heteroaryls include those illustratedabove in connection with the twelfth and thirteenth embodiments.

In a fifteenth embodiment of the compounds of structural formulae (I)and (Ia), including the above-described first through fourteenthembodiments thereof, R⁶ is hydrogen and R⁵ is an electronegative group.As will be recognized by skilled artisans, electronegative groups areatoms or groups of atoms that have a relatively great tendency toattract electrons to themselves. Specific examples of electronegativegroups according to this fourteenth embodiment include, but are notlimited to, —CN, —NC, —NO₂, halo, bromo, chloro, fluoro, (C1-C3)haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3)perfluoroalkyl, —CF₃, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3)fluoroalkoxy, (C1-C3) perfluoroalkoxy, —OCF₃, —C(O)R^(a), —C(O)OR^(a),—C(O)CF₃ and —C(O)OCF₃. In a specific embodiment, the electronegativegroup is a halogen-containing electronegative group, such as —OCF₃,—CF₃, bromo, chloro or fluoro. In another specific embodiment, R⁵ isfluoro, subject to the proviso that the compound is not any compoundaccording to the third embodiment.

In a sixteenth embodiment, the compounds of structural formulae (I) and(Ia) are compounds according to structural formula (Ib):

and salts, hydrates, solvates and N-oxides thereof, wherein R¹¹, R¹²,R¹³ and R¹⁴ are each, independently of one another, selected from thegroup consisting of hydrogen, hydroxy, (C1-C6) alkoxy and —NR^(c)R^(c);and R⁵, R⁶ and R^(c) are as previously defined for structural formula(I), with the proviso that when R¹³, R⁵ and R⁶ are each hydrogen, thenR¹¹ and R¹² are not simultaneously methoxy, (C1-C6) alkoxy or (C1-C6)haloalkoxy

In a seventeenth embodiment, the compounds of structural formulae (1)and (Ia) are compounds according to structural formula (Ic):

and salts, hydrates, solvates and N-oxides thereof, wherein:

R⁴ is selected from the group consisting of 5-10 membered heteroaryl and3-hydroxyphenyl;

R⁵ is F or —CF₃; and

R⁸ is —O(CH₂)_(m)—R^(b), where in and R^(b) are as previously definedfor structural formula (I). In a specific embodiment, R⁸ is—O—CH₂—C(O)NH—CH₃ and/or R⁴ is a heteroaryl according to the thirteenthembodiment.

In an eighteenth embodiment, the compounds of structural formulae (I)and (Ia) include any compound selected from TABLE 1 that inhibits an Fcreceptor signal transduction cascade, a Syk kinase activity, aSyk-kinase dependent receptor signal transduction cascade orcelldegranulation as measured in an in vitro assay, optionally subject tothe proviso that the compound is not a compound excluded by theabove-described third embodiment and/or other embodiments. In a specificembodiment, such compounds have an IC₅₀ of about 20 μM or less asmeasured in an in vitro degranulation assay, such as one of thedegranulation assays described in the Examples section.

In a nineteenth embodiment, the compounds of structural formulae (I) and(Ia) include any compound selected from TABLE 1 that inhibits the FcγR1or FcεR1 receptor cascade with an IC₅₀ of about 20 μM or less asmeasured in an in vitro assay, such as one of the in vitro assaysprovided in the Examples section, optionally subject to the proviso thatthe compound is not a compound excluded by the above-described thirdembodiment and/or other embodiments.

In a twentieth embodiment, the compounds of structural formulae (Ia) arethose wherein R² is selected from the group consisting of

R⁴, R⁸, R^(a), R^(b), R^(c), R^(d) are as described above, R⁵ is afluorine atom; R⁶ is a hydrogen atom and each R²¹ is independently ahalogen atoms or an alkyl optionally substituted with one or more of thesame or different halo groups, R²² and R²³ are each, independently ofone another, a hydrogen atom, methyl or ethyl optionally substitutedwith one or more of the same or different halo groups, each m isindependently an integer from 1 to 3, and each n is independently aninteger from 0 to 3.

In a twenty first embodiment, the compounds of structural formulae (Ia)are those wherein R⁴ is

wherein R⁹ and R¹⁰ are as defined above and further include, eachindependently a hydrogen atom, and R² is a phenyl group, substitutedwith one or more of the same R⁸ groups, or

wherein R³⁵ is as defined above. In one particular aspect, when R² is aphenyl group, one or more of R⁸ is selected from a halogen and an alkoxygroup. In one aspect, the phenyl group is di or tri substituted with oneor more of the same R⁸ groups.

In a twenty second embodiment, the compounds of structural formulae (Ia)are those wherein R⁴ is

and R² _(i)s a phenyl group, substituted with one or more of the same R⁸groups. In one particular aspect, one or more of R⁸ is selected from ahalogen and an alkoxy group. In one aspect, the phenyl group is di ortri substituted with one or more of the same R⁸ groups.

In a twenty third embodiment, the compounds of structural formulae (Ia)are those wherein R⁴ is a phenyl group substituted with one or more ofthe same R⁸ groups, wherein R² is

wherein R³⁵ is as defined above. In particular embodiments, the R⁴phenyl group is di or tri substituted with the same or different halgoenatoms. In another embodiment, R⁴ is a monosubstituted phenyl group witha halogen atom. In one aspect, R³⁵ is a hydroxyalkyl group. In certainaspects, the hydroxyalkyl group can be further functionalized into anester group, carbamate, etc.

In a twenty fourth embodiment, the compounds of structural formulae (Ia)are those wherein R⁴ is

wherein R³⁵ is as defined above and R² is a phenyl group substitutedwith one or more of the same R⁸ groups. In one particular aspect, R³⁵ isa hydrogen atom or an alkyl group. In another aspect, the R² phenylgroup is di or tri substituted with the same or different R⁸ groups, andin particular, halogen atoms.

In a twenty fifth embodiment, the compounds of structural formulae (Ia)are those wherein R⁴ is

wherein R³⁵ is as defined above and R² is

wherein R⁹ and R¹⁰ are defined as above and further include, eachindependently a hydrogen atom. In one aspect, R³⁵ is a hydrogen atom oran alkyl group, e.g., methyl and R⁹ and R¹⁰ are alkyl groups, e.g.,methyl groups.

In a twenty sixth embodiment, the compounds of structural formulae (Ia)are those wherein R⁴ is a disubstituted phenyl group, substituted withthe same or different R⁸ groups and R² is

wherein R³⁵ is as defined above. In certain aspects, the phenyl group issubstituted with a halogen atom and an alkyoxy group, e.g. a methoxygroup. In certain embodiments, R³⁵ is a hydrogen atom, an alkyl group,e.g., a methyl group, or a hydroxyalkyl group. In certain aspects, thehydroxyalkyl group can be further functionalized into an ester group,carbamate, etc.

In a twenty seventh embodiment, the compounds of structural formulae(Ia) are those wherein R⁴ is

wherein R⁸ and R^(c) are as defined above and R² is a phenyl group thatis substituted with one or more of the same R⁸ groups. In one particularaspect, R^(c) is a hydrogen atom or an alkyl group. In another aspect,the R² phenyl group is di or tri substituted with the same or differentR⁸ groups, and in particular, halogen atoms or

In a twenty eighth embodiment, the compounds of structural formulae (Ia)are those wherein R⁴ is

wherein Y¹, Y² and each R³⁵ independently, are defined as above and R²is

wherein R³⁵ is as defined above. In one aspect of the twenty eighthembodiment with regard to R⁴, Y¹ is oxygen, Y² is NH and one or more ofR³⁵ or the R⁴ moiety is an alkyl group, and in particular, a methylgroup. In certain aspects of the twenty eighth embodiment, two R³⁵′s ofthe R⁴ moiety form a gem dialkyl moiety, in particular, a gem dimethylmoiety adjacent to the NH depicted as

In certain aspects of the twenty eighth embodiment, with regard to R²,R³⁵ is a hydrogen atom or an alkyl group, and in particular, a methylgroup.

In a twenty nineth embodiment, the compounds of structural formulae (Ia)are those wherein R⁴ is

wherein R⁹ and R¹⁰ are as defined above or a substituted phenyl group.In one aspect the phenyl group is di or tri substituted with one or moreof the same R⁸ groups. In particular, the phenyl group can be di or trisubstituted with one or more halogen atoms that can be the same ordifferent. R² in the twenty nineth embodiment is

wherein R³⁵ is as defined above. In one aspect of the twenty ninethembodiment, R³⁵ of R² is not a methyl group. In another still anotheraspect of the twenty nineth embodiment, R² is

In a thirtieth embodiment, applicable to the first through twenty ninethembodiments, R⁵ is a halogen atom, such as fluorine, and R⁶ is ahydrogen atom.

Also specifically described are combinations of the above first throughthirtieth embodiments.

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein may include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. Indeed, many of the active 2,4-pyrimidinediaminecompounds described in TABLE 1, infra, include promoieties that arehydrolyzable or otherwise cleavable under conditions of use. Forexample, ester groups commonly undergo acid-catalyzed hydrolysis toyield the parent carboxylic acid when exposed to the acidic conditionsof the stomach, or base-catalyzed hydrolysis when exposed to the basicconditions of the intestine or blood. Thus, when administered to asubject orally, 2,4-pyrimidinediamines that include ester moieties maybe considered prodrugs of their corresponding carboxylic acid,regardless of whether the ester form is pharmacologically active.Referring to TABLE 1, numerous ester-containing 2,4-pyrimidinediaminesof the invention are active in their ester, “prodrug” form.

In the prodrugs of the invention, any available functional moiety may bemasked with a progroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that may be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.Myriad progroups suitable for masking such functional groups to yieldpromoieties that are cleavable under the desired conditions of use areknown in the art. All of these progroups, alone or in combinations, maybe included in the prodrugs of the invention.

In one illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (I) in which R^(c) and R^(d)may be, in addition to their previously-defined alternatives, aprogroup.

Replacing the hydrogens attached to N2 and N4 in the2,4-pyrimidinediamines of structural formula (1) with substituentsadversely effects the activity of the compounds. However, as will beappreciated by skilled artisans, these nitrogens may be included inpromoieties that, under conditions of use, cleave to yield2,4-pyrimidinediamines according to structural formula (I). Thus, inanother embodiment, the prodrugs of the invention are compoundsaccording to structural formula (II):

including salts, hydrates, solvates and N-oxides thereof, wherein:

R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined for structuralformula (I); and

R^(2b) and R^(4b) are each, independently of one another, a progroup.Specific examples of progroups according to this embodiment of theinvention include, but are not limited to, (C1-C6) alkyl, —C(O)CH₃,—C(O)NHR³⁶ and —S(O)₂R³⁶, where R³⁶ is (C1-C6) alkyl, (C5-C15) aryl and(C3-C8) cycloalkyl.

In the prodrugs of structural formula (II), the various substituents maybe as described for the various first through twentieth embodimentspreviously described for the compounds of structural formulae (I) and(Ia), or combinations of such embodiments.

Those of skill in the art will appreciate that many of the compounds andprodrugs of the invention, as well as the various compound speciesspecifically described and/or illustrated herein, may exhibit thephenomena of tautomerism, conformational isomerism, geometric isomerismand/or optical isomerism. For example, the compounds and prodrugs of theinvention may include one or more chiral centers and/or double bonds andas a consequence may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers and diasteromers and mixturesthereof, such as racemic mixtures. As another example, the compounds andprodrugs of the invention may exist in several tautomeric forms,including the enol form, the keto form and mixtures thereof. As thevarious compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric or geometricisomeric forms, it should be understood that the invention encompassesany tautomeric, conformational isomeric, optical isomeric and/orgeometric isomeric forms of the compounds or prodrugs having one or moreof the utilities described herein, as well as mixtures of these variousdifferent isomeric forms. In cases of limited rotation around the2,4-pryimidinediamine core structure, atrop isomers are also possibleand are also specifically included in the compounds of the invention.

Moreover, skilled artisans will appreciate that when lists ofalternative substituents include members which, owing to valencyrequirements or other reasons, cannot be used to substitute a particulargroup, the list is intended to be read in context to include thosemembers of the list that are suitable for substituting the particulargroup. For example, skilled artisans will appreciate that while all ofthe listed alternatives for R^(b) can be used to substitute an alkylgroup, certain of the alternatives, such as ═O, cannot be used tosubstitute a phenyl group. It is to be understood that only possiblecombinations of substituent-group pairs are intended.

The compounds and/or prodrugs of the invention may be identified byeither their chemical structure or their chemical name. When thechemical structure and the chemical name conflict, the chemicalstructure is determinative of the identity of the specific compound.

Depending upon the nature of the various substituents, the2,4-pyrimidinediamine compounds and prodrugs of the invention may be inthe form of salts. Such salts include salts suitable for pharmaceuticaluses (“pharmaceutically-acceptable salts”), salts suitable forveterinary uses, etc. Such salts may be derived from acids or bases, asis well-known in the art.

In one embodiment, the salt is a pharmaceutically acceptable salt.Generally, pharmaceutically acceptable salts are those salts that retainsubstantially one or more of the desired pharmacological activities ofthe parent compound and which are suitable for administration to humans.Pharmaceutically acceptable salts include acid addition salts formedwith inorganic acids or organic acids. Inorganic acids suitable forforming pharmaceutically acceptable acid addition salts include, by wayof example and not limitation, hydrohalide acids (e.g., hydrochloricacid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids suitable for formingpharmaceutically acceptable acid addition salts include, by way ofexample and not limitation, acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, palmiticacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid,ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonicacid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, cycloalkylsulfonic acids (e.g., camphorsulfonicacid), 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like.

Pharmaceutically acceptable salts also include salts formed when anacidic proton present in the parent compound is either replaced by ametal ion (e.g., an alkali metal ion, an alkaline earth metal ion or analuminum ion), an ammonium ion or coordinates with an organic base(e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine,morpholine, piperidine, dimethylamine, diethylamine, etc.).

The 2,4-pyrimidinediamine compounds and of the invention, as well as thesalts thereof, may also be in the form of hydrates, solvates andN-oxides, as are well-known in the art.

6.3 Methods of Synthesis

The compounds and prodrugs of the invention may be synthesized via avariety of different synthetic routes using commercially availablestarting materials and/or starting materials prepared by conventionalsynthetic methods. Suitable exemplary methods that may be routinelyadapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugsof the invention are found in U.S. Pat. No. 5,958,935, the disclosure ofwhich is incorporated herein by reference. Specific examples describingthe synthesis of numerous compounds and prodrugs of the invention, aswell as intermediates therefor, are provided in the Examples section.All of the compounds of structural formulae (I), (Ia) and (II) may beprepared by routine adaptation of these methods.

A variety of exemplary synthetic routes that can be used to synthesizethe 2,4-pyrimidinediamine compounds of the invention are described inSchemes (I)-(XI), below. In Schemes (I)-(XI), like-numbered compoundshave similar structures. These methods may be routinely adapted tosynthesize the prodrugs according to structural formula (11).

In one exemplary embodiment, the compounds can be synthesized fromsubstituted or unsubstituted uracils or thiouracils as illustrated inScheme (I), below:

In Scheme (I), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined forstructural formula (I), X is a halogen (e.g., F, Cl, Br or I) and Y andY′ are each, independently of one another, selected from the groupconsisting of O and S. Referring to Scheme (I), uracil or thiouracil 2is dihalogenated at the 2- and 4-positions using standard halogenatingagent POX₃ (or other standard halogenating agent) under standardconditions to yield 2,4-bishalopyrimidine 4. Depending upon the R⁵substituent, in pyrimidine 4, the halide at the C4 position is morereactive towards nucleophiles than the halide at the C2 position. Thisdifferential reactivity can be exploited to synthesize2,4-pyrimidinediamines according structural formula (I) by firstreacting 2,4-bishalopyrimidine 4 with one equivalent of amine 10,yielding 4N-substituted-2-halo-4-pyrimidineamine 8, followed by amine 6to yield a 2,4-pyrimidinediamine according structural formula (I).2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be obtainedby reacting 2,4-bishalopyrimidine 4 with excess 6 or 10, respectively.

In most situations, the C4 halide is more reactive towards nucleophiles,as illustrated in the Scheme. However, as will be recognized by skilledartisans, the identity of the R⁵ substituent may alter this reactivity.For example, when R⁵ is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine 8 and the corresponding2N-substituted-2-pyrimidineamine is obtained. Regardless of the identityof the R⁵ substituent, the regioselectivity of the reaction can becontrolled by adjusting the solvent and other synthetic conditions (suchas temperature), as is well-known in the art.

The reactions depicted in Scheme (I) may proceed more quickly when thereaction mixtures are heated via microwave. When heating in thisfashion, the following conditions may be used: heat to 175° C. inethanol for 5-20 min. in a Smith Reactor (Personal Chemistry) in asealed tube (at 20 bar pressure).

The uracil or thiouracil 2 starting materials may be purchased fromcommercial sources or prepared using standard techniques of organicchemistry. Commercially available uracils and thiouracils that can beused as starting materials in Scheme (1) include, by way of example andnot limitation, uracil (Aldrich #13,078-8; CAS Registry 66-22-8);2-thio-uracil (Aldrich #11,558-4; CAS Registry 141-90-2);2,4-dithiouracil (Aldrich #15,846-1; CAS Registry 2001-93-6);5-acetouracil (Chem. Sources Int'l 2000; CAS Registry 6214-65-9);5-azidouracil; 5-aminouracil (Aldrich #85,528-6; CAS Registry 932-52-5);5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7);5-(trans-2-bromovinyl)-uracil (Aldrich #45,744-2; CAS Registry69304-49-0); 5-(trans-2-chlorovinyl)-uracil (CAS Registry 81751-48-2);5-(trans-2-carboxyvinyl)-uracil; uracil-5-carboxylic acid(2,4-dihydroxypyrimidine-5-carboxylic acid hydrate; Aldrich #27,770-3;CAS Registry 23945-44-0); 5-chlorouracil (Aldrich #22,458-8; CASRegistry 1820-81-1); 5-cyanouracil (Chem. Sources Int'12000; CASRegistry 4425-56-3); 5-ethyluracil (Aldrich #23,044-8; CAS Registry4212-49-1); 5-ethenyluracil (CAS Registry 37107-81-6); 5-fluorouracil(Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich#85,785-8; CAS Registry 696-07-1); 5-methyluracil (thymine; Aldrich#13,199-7; CAS Registry 65-71-4); 5-nitrouracil (Aldrich #85,276-7; CASRegistry 611-08-5); uracil-5-sulfamic acid (Chem. Sources Int'12000; CASRegistry 5435-16-5); 5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CASRegistry 54-20-6); 5-(2,2,2-trifluoroethyl)-uracil (CAS Registry155143-31-6); 5-(pentafluoroethyl)-uracil (CAS Registry 60007-38-3);6-aminouracil (Aldrich #A5060-6; CAS Registry 873-83-6)uracil-6-carboxylic acid (orotic acid; Aldrich #0-840-2; CAS Registry50887-69-9); 6-methyluracil (Aldrich #D11,520-7; CAS Registry 626-48-2);uracil-5-amino-6-carboxylic acid (5-aminoorotic acid; Aldrich #19,121-3;CAS Registry #7164-43-4); 6-amino-5-nitrosouracil(6-amino-2,4-dihydroxy-5-nitrosopyrimidine; Aldrich #27,689-8; CASRegistry 5442-24-0); uracil-5-fluoro-6-carboxylic acid (5-fluorooroticacid; Aldrich #42,513-3; CAS Registry 00000-00-0); anduracil-5-nitro-6-carboxylic acid (5-nitroorotic acid; Aldrich #18,528-0;CAS Registry 600779-49-9). Additional 5-, 6- and 5,6-substituted uracilsand/or thiouracils are available from General Intermediates of Canada,Inc., Edmonton, Alberta, CA (www.generalintermediates.com) and/orInterchim, France (www.interchim.com), or may be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

Amines 6 and 10 may be purchased from commercial sources or,alternatively, may be synthesized utilizing standard techniques. Forexample, suitable amines may be synthesized from nitro precursors usingstandard chemistry. Specific exemplary reactions are provided in theExamples section. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

Skilled artisans will recognize that in some instances, amines 6 and 10and/or substituents R⁵ and/or R⁶ on uracil or thiouracil 2 may includefunctional groups that require protection during synthesis. The exactidentity of any protecting group(s) used will depend upon the identityof the functional group being protected, and will be apparent to theseof skill in the art. Guidance for selecting appropriate protectinggroups, as well as synthetic strategies for their attachment andremoval, may be found, for example, in Greene & Wuts, Protective Groupsin Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New York(1999) and the references cited therein (hereinafter “Greene & Wuts”).

A specific embodiment of Scheme (1) utilizing 5-fluorouracil (Aldrich#32,937-1) as a starting material is illustrated in Scheme (Ia), below:

In Scheme (Ia), R², R⁴, L¹ and L² are as previously defined for Scheme(I). According to Scheme (Ia), 5-fluorouracil 3 is halogenated withPOCl₃ to yield 2,4-dichloro-5-fluoropyrimidine 5, which is then reactedwith excess amine 6 or 10 to yield N2,N4-bis substituted5-fluoro-2,4-pyrimidinediamine 11 or 13, respectively. Alternatively,asymmetric 2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may beobtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with oneequivalent of amine 10 (to yield2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine 7) followed by one ormore equivalents of amine 6.

In another exemplary embodiment, the 2,4-pyrimidinediamine compounds ofthe invention may be synthesized from substituted or unsubstitutedcytosines as illustrated in Schemes (IIa) and (IIb), below:

In Schemes (Ia) and (IIb), R², R⁴, R⁵, R⁶, L¹, L² and X are aspreviously defined for Scheme (I) and PG represents a protecting group.Referring to Scheme (IIa), the C4 exocyclic amine of cytosine 20 isfirst protected with a suitable protecting group PG to yieldN4-protected cytosine 22. For specific guidance regarding protectinggroups useful in this context, see Vorbrüggen and Ruh-Pohlenz, 2001,Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp. 1-631(“Vorbrüggen”). Protected cytosine 22 is halogenated at the C2 positionusing a standard halogenation reagent under standard conditions to yield2-chloro-4N-protected-4-pyrimidineamine 24. Reaction with amine 6followed by deprotection of the C4 exocyclic amine and reaction withamine 10 yields a 2,4-pyrimidinediamine according to structural formula(I).

Alternatively, referring to Scheme (IIb), cytosine 20 may be reactedwith amine 10 or protected amine 21 to yield N4-substituted cytosine 23or 27, respectively. These substituted cytosines may then be halogenatedas previously described, deprotected (in the case of N4-substitutedcytosine 27) and reacted with amine 6 to yield a 2,4-pyrimidinediamineaccording to structural formula (1).

Commercially-available cytosines that may be used as starting materialsin Schemes (Ia) and (IIb) include, but are not limited to, cytosine(Aldrich #14,201-8; CAS Registry 71-30-7); N⁴-acetylcytosine (Aldrich#37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich#27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine.Other suitable cytosines useful as starting materials in Schemes (IIa)are available from General Intermediates of Canada, Inc., Edmonton,Alberta, CA (www.generalintermediates.com) and/or Interchim, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention may be synthesized from substituted orunsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III),below:

In Scheme (III), R², R⁴, R⁵, R⁶, L₁, L² and X are as previously definedfor Scheme (I) and Z is a leaving group as discussed in more detail inconnection with Scheme IV, infra. Referring to Scheme (III),2-amino-4-pyrimidinol 30 is reacted with amine 6 (or optionallyprotected amine 21) to yield N2-substituted-4-pyrimidinol 32, which isthen halogenated as previously described to yieldN2-substituted-4-halo-2-pyrimidineamine 34. Optional deprotection (forexample if protected amine 21 was used in the first step) followed byreaction with amine 10 affords a 2,4-pyrimidinediamine according tostructural formula (I). Alternatively, pyrimidinol 30 can be reactedwith acylating agent 31.

Suitable commercially-available 2-amino-4-pyrimidinols 30 that can beused as starting materials in Scheme (III) include, but are not limitedto, 2-amino-6-chloro-4-pyrimidinol hydrate (Aldrich #A4702-8; CASRegistry 00000-00-0) and 2-amino-6-hydroxy-4-pyrimidinol (Aldrich#A5040-1; CAS Registry 56-09-7). Other 2-amino-4-pyrimidinols 30 usefulas starting materials in Scheme (III) are available from GeneralIntermediates of Canada, Inc., Edmonton, Alberta, CA(www.generalintermediates.com) and/or Interchim, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

Alternatively, the 2,4-pyrimidinediamine compounds of the invention maybe prepared from substituted or unsubstituted 4-amino-2-pyrimidinols asillustrated in Scheme (IV), below:

In Scheme (IV), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined forScheme (I) and Z represents a leaving group. Referring to Scheme (IV),the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towardsnucleophiles than the C4-amino such that reaction with amine 6 yieldsN2-substituted-2,4-pyrimidinediamine 42. Subsequent reaction withcompound 44, which includes a good leaving group Z, or amine 10 yields a2,4-pyrimidinediamine according to structural formula (I). Compound 44may include virtually any leaving group that can be displaced by theC4-amino of N2-substituted-2,4-pyrimidinediamine 42. Suitable leavinggroups Z include, but are not limited to, halogens, methanesulfonyloxy(mesyloxy; “OMs”), trifluoromethanesulfonyloxy (“OTf”) andp-toluenesulfonyloxy (tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”)and metanitro benzene sulfonyloxy (“nosylate”). Other suitable leavinggroups will be apparent to those of skill in the art.

Substituted 4-amino-2-pyrimidinol starting materials may be obtainedcommercially or synthesized using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention can be prepared from2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines asillustrated in Scheme (V), below:

In Scheme (V), R², R⁴, R⁵, R⁶, L¹, L² and X are as defined for Scheme(I) and Z is as defined for Scheme (IV). Referring to Scheme (V),2-amino-4-chloropyrimidine 50 is reacted with amino 10 to yield4N-substituted-2-pyrimidineamine 52 which, following reaction withcompound 31 or amine 6, yields a 2,4-pyrimidinediamine according tostructural formula (I). Alternatively, 2-chloro-4-amino-pyrimidine 54may be reacted with compound 44 followed by amine 6 to yield a compoundaccording to structural formula (I).

A variety of pyrimidines 50 and 54 suitable for use as startingmaterials in Scheme (V) are commercially available, including by way ofexample and not limitation, 2-amino-4,6-dichloropyrimidine (Aldrich#A4860-1; CAS Registry 56-05-3); 2-amino-4-chloro-6-methoxy-pyrimidine(Aldrich #51,864-6; CAS Registry 5734-64-5);2-amino-4-chloro-6-methylpyrimidine (Aldrich #12,288-2; CAS Registry5600-21-5); and 2-amino-4-chloro-6-methylthiopyrimidine (Aldrich#A4600-5; CAS Registry 1005-38-5). Additional pyrimidine startingmaterials are available from General Intermediates of Canada, Inc.,Edmonton, Alberta, CA (www.generalintermediates.com) and/or Interchim,France (www.interchim.com), or may be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

Alternatively, 4-chloro-2-pyrimidineamines 50 may be prepared asillustrated in Scheme (Va):

In Scheme (Va), R⁵ and R⁶ are as previously defined for structuralformula (I). In Scheme (Va), dicarbonyl 53 is reacted with guanidine toyield 2-pyrimidineamine 51. Reaction with peracids likem-chloroperbenzoic acid, trifluoroperacetic acid or urea hydrogenperoxide complex yields N-oxide 55, which is then halogenated to give4-chloro-2-pyrimidineamine 50. The corresponding4-halo-2-pyrimidineamines may be obtained by using suitable halogenationreagents.

In yet another exemplary embodiment, the 2,4-pyrimidinediamine compoundsof the invention can be prepared from substituted or unsubstituteduridines as illustrated in Scheme (VI), below:

In Scheme (VI), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedfor Scheme (I) and the superscript PG represents a protecting group, asdiscussed in connection with Scheme (IIb). According to Scheme (VI),uridine 60 has a C4 reactive center such that reaction with amine 10 orprotected amine 21 yields N4-substituted cytidine 62 or 64,respectively. Acid-catalyzed deprotection of N4-substituted 62 or 64(when “PG” represents an acid-labile protecting group) yieldsN4-substituted cytosine 28, which may be subsequently halogenated at theC2-position and reacted with amine 6 to yield a 2,4-pyrimidinediamineaccording to structural formula (I).

Cytidines may also be used as starting materials in an analogous manner,as illustrated in Scheme (VII), below:

In Scheme (VII), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedin Scheme (I) and the superscript PG represents a protecting group asdiscussed above. Referring to Scheme (VII), like uridine 60, cytidine 70has a C4 reactive center such that reaction with amine 10 or protectedamine 21 yields N4-substituted cytidine 62 or 64, respectively. Thesecytidines 62 and 64 are then treated as previously described for Scheme(VI) to yield a 2,4-pyrimidinediamine according to structural formula(I).

Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides,skilled artisans will appreciate that the corresponding 2′-deoxyribo and2′,3′-dideoxyribo nucleosides, as well as nucleosides including sugarsor sugar analogs other than ribose, would also work.

Numerous uridines and cytidines useful as starting materials in Schemes(VI) and (VII) are known in the art, and include, by way of example andnot limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem. Sources #ABCRF07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem. Sources Int'l2000; CAS Registry 957-75-5); 5-iodo-2′-deoxyuridine (Aldrich #1-775-6;CAS Registry 54-42-2); 5-fluorouridine (Aldrich #32,937-1; CAS Registry316-46-1); 5-iodouridine (Aldrich #85,259-7; CAS Registry 1024-99-3);5-(trifluoromethyl)uridine (Chem. Sources Int'12000; CAS Registry70-00-8); 5-trifluoromethyl-2′-deoxyuridine (Chem. Sources Int'l 2000;CAS Registry 70-00-8). Additional uridines and cytidines that can beused as starting materials in Schemes (VI) and (VII) are available fromGeneral Intermediates of Canada, Inc., Edmonton, Alberta, CA(www.generalintermediates.com) and/or Interchim, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

The 2,4-pyrimidinediamine compounds of the invention can also besynthesized from substituted pyrimidines, such as chloro-substitutedpyrimidines, as illustrated in Schemes (VIII) and (IX), below:

In Schemes (VIII) and (IX), R², R⁴, L¹, L² and R^(a) are as previouslydefined for structural formula (T) and “Ar” represents an aryl group.Referring to Scheme (VIII), reaction of 2,4,6-trichloropyrimidine 80(Aldrich #T5,620-0; CAS#3764-01-0) with amine 6 yields a mixture ofthree compounds: substituted pyrimidine mono-, di- and triamines 81, 82and 83, which can be separated and isolated using HPLC or otherconventional techniques. Mono- and diamines 81 and 82 may be furtherreacted with amines 6 and/or 10 to yieldN2,N4,N6-trisubstituted-2,4,6-pyrimidinetriamines 84 and 85,respectively.

N2,N4-bis-substituted-2,4-pyrimidinediamines can be prepared in a manneranalogous to Scheme (VIII) by employing 2,4-dichloro-5-methylpyrimidineor 2,4-dichloro-pyrimidine as starting materials. In this instance, themono-substituted pyrimidineamine corresponding to compound 81 is notobtained. Instead, the reaction proceeds to yield theN2,N4-bis-substituted-2,4-pyrimidinediamine directly.

Referring to Scheme (IX), 2,4,5,6-tetrachloropyrimidine 90 (Aldrich#24,671-9; CAS #1780-40-1) is reacted with excess amine 6 to yield amixture of three compounds: 91, 92, and 93, which can be separated andisolated using HPLC or other conventional techniques. As illustrated,N2,N4-bis-substituted-5,6,-dichloro-2,4-pyrimidinediamine 92 may befurther reacted at the C6 halide with, for example a nucleophilic agent94 to yield compound 95. Alternatively, compound 92 can be convertedinto N2,N4-bis-substituted-5-chloro-6-aryl-2,4-pyrimidinediamine 97 viaa Suzuki reaction. 2,4-Pyrimidinediamine 95 may be converted to2,4-pyrimidinediamine 99 by reaction with Bn₃SnH.

As will be recognized by skilled artisans, 2,4-pyrimidinediaminesaccording to the invention, synthesized via the exemplary methodsdescribed above or by other well-known means, may also be utilized asstarting materials and/or intermediates to synthesize additional2,4-pyrimidinediamine compounds of the invention. A specific example isillustrated in Scheme (X), below:

In Scheme (X), R⁴, R⁵, R⁶, L² and R^(a) are as previously defined forstructural formula (I). Each R^(a′) is independently an R^(a), and maybe the same or different from the illustrated R^(a). Referring to Scheme(X), carboxylic acid or ester 100 may be converted to amide 104 byreaction with amine 102. In amine 102, R^(a′) may be the same ordifferent than R^(a) of acid or ester 100. Similarly, carbonate ester106 may be converted to carbamate 108.

A second specific example is illustrated in Scheme (XI), below:

In Scheme (XI), R⁴, R⁵, R⁶, L² and R^(c) are as previously defined forstructural formula (I). Referring to Scheme (XI), amide 110 or 116 maybe converted to amine 114 or 118, respectively, by borane reduction withborane methylsulfide complex 112. Other suitable reactions forsynthesizing 2,4-pyrimidinediamine compounds from 2,4-pyrimidinediaminestarting materials will be apparent to those of skill in the art.

Although many of the synthetic schemes discussed above do not illustratethe use of protecting groups, skilled artisans will recognize that insome instances substituents R², R⁴, R⁵, R⁶, L¹ and/or L² may includefunctional groups requiring protection. The exact identity of theprotecting group used will depend upon, among other things, the identityof the functional group being protected and the reaction conditions usedin the particular synthetic scheme, and will be apparent to those ofskill in the art. Guidance for selecting protecting groups andchemistries for their attachment and removal suitable for a particularapplication can be found, for example, in Greene & Wuts, supra.

Prodrugs according to structural formula (II) may be prepared by routinemodification of the above-described methods. Alternatively, suchprodrugs may be prepared by reacting a suitably protected2,4-pyrimidinediamine of structural formula (I) with a suitableprogroup. Conditions for carrying out such reactions and fordeprotecting the product to yield a prodrug of formula (II) arewell-known.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Schemes (I)-(IX),are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II”); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV”); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidine synthesis pp. 313-316; aminopyrimidine synthesis pp. 315); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall, London,UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

6.4 Inhibition of Fc Receptor Signal Cascades

Active 2,4-pyrimidinediamine compounds of the invention inhibit Fcreceptor signalling cascades that lead to, among other things,degranulation of cells. As a specific example, the compounds inhibit theFcεRI and/or FcγRI signal cascades that lead to degranulation of immunecells such as neutrophil, eosinophil, mast and/or basophil cells. Bothmast and basophil cells play a central role in allergen-induceddisorders, including, for example, allergic rhinitis and asthma.Referring to FIG. 1, upon exposure allergens, which may be, among otherthings, pollen or parasites, allergen-specific IgE antibodies aresynthesized by B-cells activated by IL-4 (or IL-13) and other messengersto switch to IgE class specific antibody synthesis. Theseallergen-specific IgEs bind to the high affinity FcεRI. Upon binding ofantigen, the FcεR1-bound IgEs are cross-linked and the IgE receptorsignal transduction pathway is activated, which leads to degranulationof the cells and consequent release and/or synthesis of a host ofchemical mediators, including histamine, proteases (e.g., tryptase andchymase), lipid mediators such as leukotrienes (e.g., LTC4),platelet-activating factor (PAF) and prostaglandins (e.g., PGD2) and aseries of cytokines, including TNF-α, IL-4, IL-13, IL-5, IL-6, IL-8,GMCSF, VEGF and TGF-β. The release and/or synthesis of these mediatorsfrom mast and/or basophil cells accounts for the early and late stageresponses induced by allergens, and is directly linked to downstreamevents that lead to a sustained inflammatory state.

The molecular events in the FcεRI signal transduction pathway that leadto release of preformed mediators via degranulation and release and/orsynthesis of other chemical mediators are well-known and are illustratedin FIG. 2. Referring to FIG. 2, the FcεRI is a heterotetrameric receptorcomposed of an IgE-binding alpha-subunit, a beta subunit, and two gammasubunits (gamma homodimer). Cross-linking of FcεRI-bound IgE bymultivalent binding agents (including, for example IgE-specificallergens or anti-IgE antibodies or fragments) induces the rapidassociation and activation of the Src-related kinase Lyn. Lynphosphorylates immunoreceptor tyrosine-based activation motifs (ITAMS)on the intracellular beta and gamma subunits, which leads to therecruitment of additional Lyn to the beta subunit and Syk kinase to thegamma homodimer. These receptor-associated kinases, which are activatedby intra- and intermolecular phosphorylation, phosphorylate othercomponents of the pathway, such as the Btk kinase, LAT, andphospholipase C-gamma PLC-gamma). Activated PLC-gamma initiates pathwaysthat lead to protein kinase C activation and Ca²⁺ mobilization, both ofwhich are required for degranulation. FcεR1 cross-linking also activatesthe three major classes of mitogen activated protein (MAP) kinases, i.e.ERK1/2, JNK1/2, and p38. Activation of these pathways is important inthe transcriptional regulation of proinflammatory mediators, such asTNF-α and IL-6, as well as the lipid mediator leukotriene CA (LTC4).

Although not illustrated, the FcγRI signaling cascade is believed toshare some common elements with the FceRI signaling cascade.Importantly, like FcεRI, the FcγRI includes a gamma homodimer that isphosphorylated and recruits Syk, and like FcεRI, activation of the FcγRIsignaling cascade leads to, among other things, degranulation. Other Fcreceptors that share the gamma homodimer, and which can be regulated bythe active 2,4-pyrimidinediamine compounds include, but are not limitedto, FcαRI and FcγRIII.

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit Fc receptor signaling cascades may be simply determined orconfirmed in in vitro assays. Suitable assays for confirming inhition ofFcεRI-mediated degranulation are provided in the Examples section. Inone typical assay, cells capable of undergoing FcεRI-mediateddegranulation, such as mast or basophil cells, are first grown in thepresence of IL-4, Stem Cell Factor (SCF), IL-6 and IgE to increaseexpression of the FcεRI, exposed to a 2,4-pyrimidinediamine testcompound of the invention and stimulated with anti-IgE antibodies (or,alternatively, an IgE-specific allergen). Following incubation, theamount of a chemical mediator or other chemical agent released and/orsynthesized as a consequence of activating the FcεRI signaling cascademay be quantified using standard techniques and compared to the amountof the mediator or agent released from control cells (i.e., cells thatare stimulated but that are not exposed to test compound). Theconcentration of test compound that yields a 50% reduction in thequantity of the mediator or agent measured as compared to control cellsis the IC₅₀ of the test compound. The origin of the mast or basophilcells used in the assay will depend, in part, on the desired use for thecompounds and will be apparent to those of skill in the art. Forexample, if the compounds will be used to treat or prevent a particulardisease in humans, a convenient source of mast or basophil cells is ahuman or other animal which constitutes an accepted or known clinicalmodel for the particular disease. Thus, depending upon the particularapplication, the mast or basophil cells may be derived from a widevariety of animal sources, ranging from, for example, lower mammals suchas mice and rats, to dogs, sheep and other mammals commonly employed inclinical testing, to higher mammals such as monkeys, chimpanzees andapes, to humans. Specific examples of cells suitable for carrying outthe in vitro assays include, but are not limited to, rodent or humanbasophil cells, rat basophil leukemia cell lines, primary mouse mastcells (such as bone marrow-derived mouse mast cells “BMMC”) and primaryhuman mast cells isolated from cord blood (“CHMC”) or other tissues suchas lung. Methods for isolating and culturing these cell types arewell-known or are provided in the Examples section (see, e.g., Demo etal., 1999, Cytometry 36(4):340-348 and copending application Serial No.10/053,355, filed Nov.8, 2001, the disclosures of which are incorporatedherein by reference). Of course, other types of immune cells thatdegranulate upon activation of the FcεRI signaling cascade may also beused, including, for example, eosinophils.

As will be recognized by skilled artisans, the mediator or agentquantified is not critical. The only requirement is that it be amediator or agent released and/or synthesized as a consequence ofinitiating or activating the Fc receptor signaling cascade. For example,referring to FIG. 1, activation of the FcεRI signaling cascade in mastand/or basophil cells leads to numerous downstream events. For example,activation of the FcεRI signal cascade leads to the immediate release(i.e., within 1-3 min. following receptor activation) of a variety ofpreformed chemical mediators and agents via degranulation. Thus, in oneembodiment, the mediator or agent quantified may be specific to granules(i.e., present in granules but not in the cell cytoplasm generally).Examples of granule-specific mediators or agents that can be quantifiedto determine and/or confirm the activity of a 2,4-pyrimidinediaminecompound of the invention include, but are not limited to,granule-specific enzymes such as hexosaminidase and tryptase andgranule-specific components such as histamine and serotonin. Assays forquantifying such factors are well-known, and in many instances arecommercially available. For example, tryptase and/or hexosaminidaserelease may be quantified by incubating the cells with cleavablesubstrates that fluoresce upon cleavage and quantifying the amount offluorescence produced using conventional techniques. Such cleavablefluorogenic substrates are commercially available. For example, thefluorogenic substrates Z-Gly-Pro-Arg-AMC (Z=benzyloxycarbonyl;AMC=7-amino-4-methylcoumarin; BIOMOL Research Laboratories, Inc.,Plymouth Meeting, Pa. 19462, Catalog No. P-142) and Z-Ala-Lys-Arg-AMC(Enzyme Systems Products, a division of ICN Biomedicals, Inc.,Livermore, Calif. 94550, Catalog No. AMC-246) can be used to quantifythe amount of tryptase released. The fluorogenic substrate4-methylumbelliferyl-N-acetyl-β-D-glucosaminide (Sigma, St. Louis, Mo.,Catalog #69585) can be used to quantify the amount of hexosaminidasereleased. Histamine release may be quantified using a commerciallyavailable enzyme-linked immunosorbent assay (ELISA) such as Immunotechhistamine ELISA assay #IM2015 (Beckman-Coulter, Inc.). Specific methodsof quantifying the release of tryptase, hexosaminidase and histamine areprovided in the Examples section. Any of these assays may be used todetermine or confirm the activity of the 2,4-pyrimidinediamine compoundsof the invention.

Referring again to FIG. 1, degranulation is only one of severalresponses initiated by the FcεRI signaling cascade. In addition,activation of this signaling pathway leads to the de novo synthesis andrelease of cytokines and chemokines such as IL-4, IL-5, IL-6, TNF-α,IL-13 and MIP1-α), and release of lipid mediators such as leukotrienes(e.g., LTC4), platelet activating factor (PAF) and prostaglandins.Accordingly, the 2,4-pyrimidinediamine compounds of the invention mayalso be assessed for activity by quantifying the amount of one or moreof these mediators released and/or synthesized by activated cells.

Unlike the granule-specific components discussed above, these “latestage” mediators are not released immediately following activation ofthe FcεRI signaling cascade. Accordingly, when quantifying these latestage mediators, care should be taken to insure that the activated cellculture is incubated for a time sufficient to result in the synthesis(if necessary) and release of the mediator being quantified. Generally,PAF and lipid mediators such as leukotriene C4 are released 3-30 min.following FcεRI activation. The cytokines and other late stage mediatorsare released approx. 4-8 hrs. following FcεRI activation. Incubationtimes suitable for a specific mediator will be apparent to those ofskill in the art. Specific guidance and assays are provided in theExamples section.

The amount of a particular late stage mediator released may bequantified using any standard technique. In one embodiment, theamount(s) may be quantified using ELISA assays. ELISA assay kitssuitable for quantifying the amount of TNFα, IL-4, IL-5, IL-6 and/orIL-13 released are available from, for example, Biosource International,Inc., Camarillo, Calif. 93012 (see, e.g., Catalog Nos. KHC3011, KHC0042,KHC0052, KHC0061 and KHC0132). ELISA assay kits suitable for quantifyingthe amount of leukotriene C4 (LTC4) released from cells are availablefrom Cayman Chemical Co., Ann Arbor, Mich. 48108 (see, e.g., Catalog No.520211).

Typically, active 2,4-pyrimidinediamine compounds of the invention willexhibit IC₅₀s with respect to FcεRI-mediated degranulation and/ormediator release or synthesis of about 20 μM or lower, as measured in anin vitro assay, such as one of the in vitro assays described above or inthe Examples section. Of course, skilled artisans will appreciate thatcompounds which exhibit lower IC₅₀s, for example on the order of 10 μM,1 μM, 100 nM, 10 nM, 1 nM, or even lower, are particularly useful.

Skilled artisans will also appreciate that the various mediatorsdiscussed above may induce different adverse effects or exhibitdifferent potencies with respect to the same adverse effect. Forexample, the lipid mediator LTC4 is a potent vasoconstrictor—it isapproximately 1000-fold more potent at inducing vasoconstriction thanhistamine. As another example, in addition to mediating atopic or Type Ihypersensitivity reactions, cytokines can also cause tissue remodelingand cell proliferation. Thus, although compounds that inhibit releaseand/or synthesis of any one of the previously discussed chemicalmediators are useful, skilled artisans will appreciate that compoundswhich inhibit the release and/or synthesis of a plurality, or even all,of the previously described mediators find particular use, as suchcompounds are useful for ameliorating or avoiding altogether aplurality, or even all, of the adverse effects induced by the particularmediators. For example, compounds which inhibit the release of all threetypes of mediators—granule-specific, lipid and cytokine—are useful fortreating or preventing immediate Type I hypersensitivity reactions aswell as the chronic symptoms associated therewith.

Compounds of the invention capable of inhibiting the release of morethan one type of mediator (e.g., granule-specific or late stage) may beidentified by determining the IC₅₀ with respect to a mediatorrepresentative of each class using the various in vitro assays describedabove (or other equivalent in vitro assays). Compounds of the inventionwhich are capable of inhibiting the release of more than one mediatortype will typically exhibit an IC₅₀ for each mediator type tested ofless than about 20 μM. For example, a compound) which exhibits an IC₅₀of 1 μM with respect to histamine release (IC₅₀ ^(histamine)) and anIC₅₀ of 1 nM with respect to leukotriene LTC4 synthesis and/or release(IC₅₀ ^(LTC4)) inhibits both immediate (granule-specific) and late stagemediator release. As another specific example, a compound that exhibitsan IC₅₀ ^(tryptase) of 10 μM, and IC₅₀ ^(LTC4) of 1 μM and an IC₅₀^(IL-4) of 1 μM inhibits immediate (granule-specific), lipid andcytokine mediator release. Although the above specific examples utilizethe IC₅₀s of one representative mediator of each class, skilled artisanswill appreciate that the IC₅₀s of a plurality, or even all, mediatorscomprising one or more of the classes may be obtained. The quantity(ies)and identity(ies) of mediators for which IC₅₀ data should be ascertainedfor a particular compound and application will be apparent to those ofskill in the art.

Similar assays may be utilized to confirm inhibition of signaltransduction cascades initiated by other Fc receptors, such as FcαRI,FcγRI and/or FcγRIII signaling, with routine modification. For example,the ability of the compounds to inhibit FcγRI signal transduction may beconfirmed in assays similar to those described above, with the exceptionthat the FcγRI signaling cascade is activated, for example by incubatingthe cells with IgG and an IgG-specific allergen or antibody, instead ofIgE and an IgE-specific allergen or antibody. Suitable cell types,activating agents and agents to quantify to confirm inhibition of otherFc receptors, such as Fc receptors that comprise a gamma homodimer, willbe apparent to those of skill in the art.

One particularly useful class of compounds includes those2,4-pyrimidinediamine compounds that inhibit the release of immediategranule-specific mediators and late stage mediators with approximatelyequivalent IC₅₀s. By approximately equivalent is meant that the IC₅₀sfor each mediator type are within about a 10-fold range of one another.Another particularly useful class of compounds includes those2,4-pyrimidinediamine compounds that inhibit the release of immediategranule-specific mediators, lipid mediators and cytokine mediators withapproximately equivalent IC₅₀s. In a specific embodiment, such compoundsinhibit the release of the following mediators with approximatelyequivalent IC₅₀s: histamine, tryptase, hexosaminidase, IL-4, IL-5, IL-6,IL-13, TNFα and LTC4. Such compounds are particularly useful for, amongother things, ameliorating or avoiding altogether both the early andlate stage responses associated with atopic or immediate Type Ihypersensitivity reactions.

Ideally, the ability to inhibit the release of all desired types ofmediators will reside in a single compound. However, mixtures ofcompounds can also be identified that achieve the same result. Forexample, a first compound which inhibits the release of granule specificmediators may be used in combination with a second compound whichinhibits the release and/or synthesis of cytokine mediators.

In addition to the FcεRI or FcγRI degranulation pathways discussedabove, degranulation of mast and/or basophil cells can be induced byother agents. For example, ionomycin, a calcium ionophore that bypassesthe early FcεRI or FcγRI signal transduction machinery of the cell,directly induces a calcium flux that triggers degranulation. Referringagain to FIG. 2, activated PLCγ initiates pathways that lead to, amongother things, calcium ion mobilization and subsequent degranulation. Asillustrated, this Ca²⁺ mobilization is triggered late in the FcεRIsignal transduction pathway. As mentioned above, and as illustrated inFIG. 3, ionomycin directly induces Ca²⁺ mobilization and a Ca²⁺ fluxthat leads to degranulation. Other ionophores that induce degranulationin this manner include A23187. The ability of granulation-inducingionophores such as ionomycin to bypass the early stages of the FcεRIand/or FcγRI signaling cascades may be used as a counter screen toidentify active compounds of the invention that specifically exert theirdegranulation-inhibitory activity by blocking or inhibiting the earlyFcεRI or FcγRI signaling cascades, as discussed above. Compounds whichspecifically inhibit such early FcεRI or FcγRI-mediated degranulationinhibit not only degranulation and subsequent rapid release ofhistamine, tryptase and other granule contents, but also inhibit thepro-inflammatory activation pathways causing the release of TNFα, IL-4,IL-13 and the lipid mediators such as LTC4. Thus, compounds whichspecifically inhibit such early FcεRI and/or FcγRI-mediateddegranulation block or inhibit not only acute atopic or Type Ihypersensitivity reactions, but also late responses involving multipleinflammatory mediators.

Compounds of the invention that specifically inhibit early FcεRI and/orFcγRI-mediated degranulation are those compounds that inhibit FcεRIand/or FcγRI-mediated degranulation (for example, have an IC₅₀ of lessthan about 20 μM with respect to the release of a granule-specificmediator or component as measured in an in vitro assay with cellsstimulated with an IgE or IgG binding agent) but that do not appreciablyinhibit ionophore-induced degranulation. In one embodiment, compoundsare considered to not appreciably inhibit ionophore-induceddegranulation if they exhibit an IC₅₀ of ionophore-induced degranulationof greater than about 20 μM as measured in an in vitro assay. Of course,active compounds that exhibit even higher IC₅₀s of ionophore-induceddegranulation, or that do not inhibit ionophore-induced degranulation atall, are particularly useful. In another embodiment, compounds areconsidered to not appreciably inhibit ionophore-induced degranulation ifthey exhibit a greater than 10-fold difference in their IC₅₀s of FcεRIand/or FcγRI-mediated degranulation and ionophore-induced degranulation,as measured in an in vitro assay. Assays suitable for determining theIC₅₀ of ionophore-induced degranulation include any of thepreviously-described degranulation assays, with the modification thatthe cells are stimulated or activated with a degranulation-inducingcalcium ionophore such as ionomycin or A23187 (A.G. Scientific, SanDiego, Calif.) instead of anti-IgE antibodies or an IgE-specificallergen. Specific assays for assessing the ability of a particular2,4-pyrimidinediamine compound of the invention to inhibitionophore-induced degranulation are provided in the Examples section.

As will be recognized by skilled artisans, compounds which exhibit ahigh degree of selectivity of FcεRI-mediated degranulation findparticular use, as such compounds selectively target the FcεRI cascadeand do not interfere with other degranulation mechanisms. Similarly,compounds which exhibit a high degree of selectivity of FcγRI-mediateddegranulation find particular use, as such compounds selectively targetthe FcγRI cascade and do not interfere with other degranulationmechanisms. Compounds which exhibit a high degree of selectivity aregenerally 10-fold or more selective for FcεRI- or FcγRI-mediateddegranulation over ionophore-induced degranulation, such asionomycin-induced degranulation.

Biochemical and other data confirm that the 2,4-pyrimidinediaminecompounds described herein are potent inhibitors of Syk kinase activity.For example, in experiments with an isolated Syk kinase, of twenty four2,4-pyrimidinediamine compounds tested, all but two inhibited the Sykkinase catalyzed phosphorylation of a peptide substrate with IC50s inthe submicromolar range. The remaining compounds inhibitedphosphorylation in the micromolar range. In addition, of sixteencompounds tested in an in vitro assay with mast cells, all inhibitedphosphorylation of Syk kinase substrates (e.g., PLC-gammal, LAT) andproteins downstream of Syk kinase (e.g., JNK, p38, Erk1/2 and PKB, whentested), but not proteins upstream of Syk kinase in the cascade (e.g.,Lyn). Phosphorylation of Lyn substrates was not inhibited by the2,4-pyrimidinediamine compounds tested. Moreover, for the followingcompounds, a high correlation was observed between their inhibition ofSyk kinase activity in biochemical assays (IC₅₀s in the range of 3 to1850 nM) and their inhibition of FcεR1-mediated degranulation in mastcells (IC₅₀s in the range of 30 to 1650 nM): R950373, R950368, R921302,R945371, R945370, R945369, R945365, R921304, R945144, R945140, R945071,R940358, R940353, R940352, R940351, R940350, R940347, R921303, R940338,R940323, R940290, R940277, R940276, R940275, R940269, R940255, R935393,R935372, R935366, R935310, R935309, R935307, R935304, R935302, R935293,R935237, R935198, R935196, R935194, R935193, R935191, R935190, R935138,R927050, R926968, R926956, R926931, R926891, R926839, R926834, R926816,R926813, R926791, R926782, R926780, R926757, R926753, R926745, R926715,R926508, R926505, R926502, R926501, R926500, R921218, R921147, R920410,R909268, R921219, R908712, R908702.

Accordingly, the activity of the 2,4-pyrimidinediamine compounds of theinvention may also be confirmed in biochemical or cellular assays of Sykkinase activity. Referring again to FIG. 2, in the FcεRI signalingcascade in mast and/or basophil cells, Syk kinase phosphorylates LAT andPLC-gammal, which leads to, among other things, degranulation. Any ofthese activities may be used to confirm the activity of the2,4-pyrimidinediamine compounds of the invention. In one embodiment, theactivity is confirmed by contacting an isolated Syk kinase, or an activefragment thereof with a 2,4-pyrimidinediamine compound in the presenceof a Syk kinase substrate (e.g., a synthetic peptide or a protein thatis known to be phophorylated by Syk in a signaling cascade) andassessing whether the Syk kinase phosphorylated the substrate.Alternatively, the assay may be carried out with cells that express aSyk kinase. The cells may express the Syk kinase endogenously or theymay be engineered to express a recombinant Syk kinase. The cells mayoptionally also express the Syk kinase substrate. Cells suitable forperforming such confirmation assays, as well as methods of engineeringsuitable cells will be apparent to those of skill in the art. Specificexamples of biochemical and cellular assays suitable for confirming theactivity of the 2,4-pyrimidinediamine compounds are provided in theExamples section.

Generally, compounds that are Syk kinase inhibitors will exhibit an IC₅₀with respect to a Syk kinase activity, such as the ability of Syk kinaseto phosphorylate a synthetic or endogenous substrate, in an in vitro orcellular assay in the range of about 20 μM or less. Skilled artisanswill appreciate that compounds that exhibit lower IC50s, such as in therange of 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, or even lower, areparticularly useful.

6.5 Uses and Compositions

As previously discussed, the active compounds of the invention inhibitFc receptor signaling cascades, especially those Fc receptors includinga gamma homodimer, such as the FcεRI and/or FcγRI signaling cascades,that lead to, among other things, the release and/or synthesis ofchemical mediators from cells, either via degranulation or otherprocesses. As also discussed, the active compounds are also potentinhibitors of Syk kinase. As a consequence of these activities, theactive compounds of the invention may be used in a variety of in vitro,in vivo and ex vivo contexts to regulate or inhibit Syk kinase,signaling cascades in which Syk kinase plays a role, Fc receptorsignaling cascades, and the biological responses effected by suchsignaling cascades. For example, in one embodiment, the compounds may beused to inhibit Syk kinase, either in vitro or in vivo, in virtually anycell type expressing Syk kinase. They may also be used to regulatesignal transduction cascades in which Syk kinase plays a role. SuchSyk-dependent signal transduction cascades include, but are not limitedto, the FcεRI, FcγRI, FcγRIII, BCR and integrin signal transductioncascades. The compounds may also be used in vitro or in vivo toregulate, and in particular inhibit, cellular or biological responseseffected by such Syk-dependent signal transduction cascades. Suchcellular or biological responses include, but are not limited to,respiratory burst, cellular adhesion, cellular degranulation, cellspreading, cell migration, cell aggregation, phageytosis, cytokinesynthesis and release, cell maturation and Ca²⁻ flux. Importantly, thecompounds may be used to inhibit Syk kinase in vivo as a therapeuticapproach towards the treatment or prevention of diseases mediated,either wholly or in part, by a Syk kinase activity. Non-limitingexamples of Syk kinase mediated diseases that may be treated orprevented with the compounds are those discussed in more detail, below.

In another embodiment, the active compounds may be used to regulate orinhibit the Fc receptor signaling cascades and/or FcεRI- and/orFcγRI-mediated degranulation as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by and/orassociated with the release or synthesis of chemical mediators of suchFc receptor signaling cascades or degranulation. Such treatments may beadministered to animals in veterinary contexts or to humans. Diseasesthat are characterized by, caused by or associated with such mediatorrelease, synthesis or degranulation, and that can therefore be treatedor prevented with the active compounds include, by way of example andnot limitation, atopy or anaphylactic hypersensitivity or allergicreactions, allergies (e.g., allergic conjunctivitis, allergic rhinitis,atopic asthma, atopic dermatitis and food allergies), low grade scarring(e.g., of scleroderma, increased fibrosis, keloids, post-surgical scars,pulmonary fibrosis, vascular spasms, migraine, reperfusion injury andpost myocardial infarction), diseases associated with tissue destruction(e.g., of COPD, cardiobronchitis and post myocardial infarction),diseases associated with tissue inflammation (e.g., irritable bowelsyndrome, spastic colon and inflammatory bowel disease), inflammationand scarring.

In addition to the myriad diseases discussed above, cellular and animalempirical data confirm that the 2,4-pyrimidinediamine compoundsdescribed herein are also useful for the treatment or prevention ofautoimmune diseases, as well as the various symptoms associated withsuch diseases. The types of autoimmune diseases that may be treated orprevented with the 2,4-pyrimidinediamine compounds generally includethose disorders involving tissue injury that occurs as a result of ahumoral and/or cell-mediated response to immunogens or antigens ofendogenous and/or exogenous origin. Such diseases are frequentlyreferred to as diseases involving the nonanaphylactic (i.e., Type II,Type III and/or Type IV) hypersensitivity reactions.

As discussed previously, Type I hypersensitivity reactions generallyresult from the release of pharmacologically active substances, such ashistamine, from mast and/or basophil cells following contact with aspecific exogenous antigen. As mentioned above, such Type I reactionsplay a role in numerous diseases, including allergic asthma, allergicrhinitis, etc.

Type II hypersensitivity reactions (also referred to as cytotoxic,cytolytic complement-dependent or cell-stimulating hypersensitivityreactions) result when immunoglobulins react with antigenic componentsof cells or tissue, or with an antigen or hapten that has becomeintimately coupled to cells or tissue. Diseases that are commonlyassociated with Type II hypersensitivity reactions include, but are notlimited, to autoimmune hemolytic anemia, erythroblastosis fetalis andGoodpasture's disease.

Type III hypersensitivity reactions, (also referred to as toxic complex,soluble complex, or immune complex hypersensitivity reactions) resultfrom the deposition of soluble circulating antigen-immunoglobulincomplexes in vessels or in tissues, with accompanying acute inflammatoryreactions at the site of immune complex deposition. Non-limitingexamples of prototypical Type III reaction diseases include the Arthusreaction, rheumatoid arthritis, serum sickness, systemic lupuserythematosis, certain types of glomerulonephritis, multiple sclerosisand bullous pemphingoid.

Type IV hypersensitivity reactions (frequently called cellular,cell-mediated, delayed, or tuberculin-type hypersensitivity reactions)are caused by sensitized T-lymphocytes which result from contact with aspecific antigen. Non-limiting examples of diseases cited as involvingType IV reactions are contact dermatitis and allograft rejection.

Autoimmune diseases associated with any of the above nonanaphylactichypersensitivity reactions may be treated or prevented with the2,4-pyrimidinediamine compounds of the invention. In particular, themethods may be used to treat or prevent those autoimmune diseasesfrequently characterized as single organ or single cell-type autoimmunedisorders including, but not limited to: Hashimoto's thyroiditis,autoimmune hemolytic anemia, autoimmune atrophic gastritis of perniciousanemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture'sdisease, autoimmune thrombocytopenia, sympathetic ophthalmia, myastheniagravis, Graves' disease, primary biliary cirrhosis, chronic aggressivehepatitis, ulcerative colitis and membranous glomerulopathy, as well asthose autoimmune diseases frequently characterized as involving systemicautoimmune disorder, which include but are not limited to: systemiclupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter'ssyndrome, polymyositis-dermatomyositis, systemic sclerosis,polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.

It will be appreciated by skilled artisans that many of the above-listedautoimmune diseases are associated with severe symptoms, theamelioration of which provides significant therapeutic benefit even ininstances where the underlying autoimmune disease may not beameliorated. Many of these symptoms, as well as their underlying diseasestates, result as a consequence of activating the FcγR signaling cascadein monocyte cells. As the 2,4-pyrimidinediamine compounds describedherein are potent inhibitors of such FcγR signaling in monocytes andother cells, the methods find use in the treatment and/or prevention ofmyriad adverse symptoms associated with the above-listed autoimmunediseases.

As a specific example, rheumatoid arthritis (RA) typically results inswelling, pain, loss of motion and tenderness of target jointsthroughout the body. RA is characterized by chronically inflamedsynovium that is densely crowded with lymphocytes. The synovialmembrane, which is typically one cell layer thick, becomes intenselycellular and assumes a form similar to lymphoid tissue, includingdentritic cells, T-, B- and NK cells, macrophages and clusters of plasmacells. This process, as well as a plethora of immunopathologicalmechanisms including the formation of antigen-immunoglobulin complexes,eventually result in destruction of the integrity of the joint,resulting in deformity, permanent loss of function and/or bone erosionat or near the joint. The methods may be used to treat or ameliorate anyone, several or all of these symptoms of RA. Thus, in the context of RA,the methods are considered to provide therapeutic benefit (discussedmore generally, infra) when a reduction or amelioration of any of thesymptoms commonly associated with RA is achieved, regardless of whetherthe treatment results in a concomitant treatment of the underlying RAand/or a reduction in the amount of circulating rheumatoid factor(“RF”).

As another specific example, systemic lupus erythematosis (“SLE”) istypically associated with symptoms such as fever, joint pain(arthralgias), arthritis, and serositis (pleurisy or pericarditis). Inthe context of SLE, the methods are considered to provide therapeuticbenefit when a reduction or amelioration of any of the symptoms commonlyassociated with SLE are achieved, regardless of whether the treatmentresults in a concomitant treatment of the underlying SLE.

As another specific example, multiple sclerosis (“MS”) cripples thepatient by disturbing visual acuity; stimulating double vision;disturbing motor functions affecting walking and use of the hands;producing bowel and bladder incontinence; spasticity; and sensorydeficits (touch, pain and temperature sensitivity). In the context ofMS, the methods are considered to provide therapeutic benefit when animprovement or a reduction in the progression of any one or more of thecrippling effects commonly associated with MS is achieved, regardless ofwhether the treatment results in a concomitant treatment of theunderlying MS.

When used to treat or prevent such diseases, the active compounds may beadministered singly, as mixtures of one or more active compounds or inmixture or combination with other agents useful for treating suchdiseases and/or the symptoms associated with such diseases. The activecompounds may also be administered in mixture or in combination withagents useful to treat other disorders or maladies, such as steroids,membrane stablizers, 5LO inhibitors, leukotriene synthesis and receptorinhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgGisotype switching or IgG synthesis, β-agonists, tryptase inhibitors,aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to namea few. The active compounds may be administered per se in the form ofprodrugs or as pharmaceutical compositions, comprising an activecompound or prodrug.

Pharmaceutical compositions comprising the active compounds of theinvention (or prodrugs thereof) may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making levigating,emulsifying, encapsulating, entrapping or lyophilization processes. Thecompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active compounds into preparationswhich can be used pharmaceutically.

The active compound or prodrug may be formulated in the pharmaceuticalcompositions per se, or in the form of a hydrate, solvate, N-oxide orpharmaceutically acceptable salt, as previously described. Typically,such salts are more soluble in aqueous solutions than the correspondingfree acids and bases, but salts having lower solubility than thecorresponding free acids and bases may also be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, transdermal,rectal, vaginal, etc., or a form suitable for administration byinhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) may beformulated as solutions, gels, ointments, creams, suspensions, etc. asare well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, etc., before use.To this end, the active compound(s) may be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings. Compoundswhich are particularly suitable for oral administration includeCompounds R940350, R935372, R935193, R927050 and R935391.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases such as cocoa butteror other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5-20mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH5 to pH7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation, and in particular forsuch administration of Compound R921218, contains 1-20 mg/mL Compound orprodrug, 0.1-1% (v/v) Polysorbate 80 (TWEEN®80), 50 mM citrate and/or0.9% sodium chloride.

For ocular administration, the active compound(s) or prodrug(s) may beformulated as a solution, emulsion, suspension, etc. suitable foradministration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. No. 6,261,547; U.S.Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807;U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No.5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat.No. 4,882,150; and U.S. Pat. No. 4,738,851.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient may be formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. No. 5,407,713.; U.S.Pat. No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168;U.S. Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No.5,164,189; U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat.No. 5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

6.6 Effective Dosages

The active compound(s) or prodrug(s) of the invention, or compositionsthereof, will generally be used in an amount effective to achieve theintended result, for example in an amount effective to treat or preventthe particular disease being treated. The compound(s) may beadministered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmaticattack, or a reduction in the frequency or severity of asthmaticepisodes. Therapeutic benefit also includes halting or slowing theprogression of the disease, regardless of whether improvement isrealized.

For prophylactic administration, the compound may be administered to apatient at risk of developing one of the previously described diseases.For example, if it is unknown whether a patient is allergic to aparticular drug, the compound may be administered prior toadministration of the drug to avoid or ameliorate an allergic responseto the drug. Alternatively, prophylactic administration may be appliedto avoid the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a compound may be administered to anallergy sufferer prior to expected exposure to the allergen. Compoundsmay also be administered prophylactically to healthy individuals who arerepeatedly exposed to agents known to one of the above-describedmaladies to prevent the onset of the disorder. For example, a compoundmay be administered to a healthy individual who is repeatedly exposed toan allergen known to induce allergies, such as latex, in an effort toprevent the individual from developing an allergy. Alternatively, acompound may be administered to a patient suffering from asthma prior topartaking in activities which trigger asthma attacks to lessen theseverity of, or avoid altogether, an asthmatic episode.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, etc. Determination of an effectivedosage is well within the capabilities of those skilled in the art.

Effective dosages may be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals may be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in asin vitro assay, such as the in vitro CHMC or BMMC and other in vitroassays described in the Examples section. Calculating dosages to achievesuch circulating blood or serum concentrations taking into account thebioavailability of the particular compound is well within thecapabilities of skilled artisans. For guidance, the reader is referredto Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, 1995, Allergy 50(21Suppl):6-9,discussion 34-38 and Tumas et al., 2001, J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., 2000, Arzneimittelforschung50(11):1037-42; Kawaguchi et al., 1994, Clin. Exp. Allergy 24(3):238-244and Sugimoto et al., 2000, Immunopharmacology 48(1):1-7. Suitable animalmodels of allergic conjunctivitis are described in Carreras et al.,1993, Br. J. Ophthalmol. 77(8):509-514; Saiga et al., 1992, OphthalmicRes. 24(1):45-50; and Kunert et al., 2001, Invest. Ophthalmol. Vis. Sci.42(11):2483-2489. Suitable animal models of systemic mastocytosis aredescribed in O'Keefe et al., 1987, J. Vet. Intern. Med. 1(2):75-80 andBean-Knudsen et al., 1989, Vet. Pathol. 26(1):90-92. Suitable animalmodels of hyper IgE syndrome are described in Claman et al., 1990, Clin.Immunol. Immunopathol. 56(1):46-53. Suitable animal models of B-celllymphoma are described in Hough et al., 1998, Proc. Natl. Acad. Sci. USA95:13853-13858 and Hakim et al., 1996, J. Immunol. 157(12):5503-5511.Suitable animal models of atopic disorders such as atopic dermatitis,atopic eczema and atopic asthma are described in Chan et al., 2001, J.Invest. Dermatol. 117(4):977-983 and Suto et al., 1999, Int. Arch.Allergy Immunol. 120(Suppl 1):70-75. Ordinarily skilled artisans canroutinely adapt such information to determine dosages suitable for humanadministration. Additional suitable animal models are described in theExamples section.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration and variousfactors discussed above. Dosage amount and interval may be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. For example,the compounds may be administered once per week, several times per week(e.g., every other day), once per day or multiple times per day,depending upon, among other things, the mode of administration, thespecific indication being treated and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) may be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The invention having been described, the following examples are offeredby way of illustration and not limitation.

7. EXAMPLES

7.1 Synthesis of Starting Materials and Intermediates Useful forSynthesizing The 2,4-Pyrimidinediamine Compounds According to Schemes(I)-(V)

A variety of starting materials andN4-monosubstituted-2-pyrimidineamines andN2-monosubstituted-4-pyrimidinediamines [mono Substitution NucleophilicAromatic Reaction (SNAR) products] useful for synthesizing the2,4-pyrimidinediamine compounds of the invention according to Schemes(I)-(V) were prepared as described below. Conditions suitable forsynthesizing the mono SNAR products are exemplified with2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine(R926087).

Section Number Name of compound and reference number Experimental 7.1Synthesis of Starting Materials and Intermediates Useful forSynthesizing The 2,4-Pyrimidinediamine Compounds According to Schemes(I)-(V) A variety of starting materials andN4-monosubstituted-2-pyrimidineamines andN2-monosubstituted-4-pyrimidinediamines [mono Substitution NucleophilicAromatic Reaction (SNAR) prfoducts]useful for synthesizing the2,4-pyrimidinediamine compounds of the invention according to Schemes(I)-(V) were prepared as described below. Conditions suitable forsynthesizing the mono SNAR products are exemplified with2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine(R926087) 7.1.1 2,4-Dichloro-5-fluoropyrimidine To a dry reaction flaskequipped with a stir bar and a reflux condenser was placed5-fluorouracil (0.65 g, 5mmol) followed by phosphorus oxychloride(POCl₃) (1.53 g, 10mmol). The resultant mixture was heated at 110° C.for 8 hours under a nitrogen atmosphere. The reaction was cooled to roomtemperature, phosphorus pentachloride (PCl₅) (3.12 g, 15mmol) was addedand heated to 110° C. for a period of 12 hours. After cooling to roomtemperature, the mixture was poured into ice-water, saturated withsodium chloride and left for 1 hour at 0° C. to complete thedecomposition of POCl₃ and PCl₅. The solid of2,4-dichloro-5-fluoropyrimidine was collected by rapid filtration, driedusing blotting paper and stored at low temperature. ¹H NMR (CDCl₃):δ8.47 (s, 1H); ¹³C NMR (CDCl₃): δ155.42, 151.87, 147.43 and 147.13; ¹⁹FNMR (CDCl₃): - 38149. 7.1.2 2,4-Dichloro-5-nitropyrimidine (Aldrich D6,930-0) A suspension of 5-nitrouracil (10 g, 63 mmol) in POCl₃ (100 mL)was refluxed for 5 h in the presence of N,N-dimethylaniline (10 mL),cooled to room temperature and poured on to crushed ice with vigorousstirring. The aqueous layer was extracted with ethyl acetate. Thecombined organic layers were dried over MgSO₄ and the solvent wasevaporated under reduce pressure. The residue was purified bychromatography on silica gel (hexane/ethyl acetate; 1/1; v/v) to givethe desired 2,4-dichloro-5-nitropyrimidine. LCMS: ret. time: 23.26 min.;purity: 95%; ¹H NMR (CDCl₃): δ9.16 (1H, s). 7.1.32,4-Dichloro-5-cyanopyrimidine In like manner to the preparation of2,4-dichloro-5-nitropyrimidine, the reaction of 5-cyanouracil with POCl₃and N,N-dimethylaniline gave 2,4-dichloro-5-cyanopyrimidine. LCMS: ret.time: 13.75 min.; purity: 95%. 7.1.42,4-Dichloro-5-trifluoromethylpyrimidine In like manner to thepreparation of 2,4-dichloro-5-nitropyrimidine, the reaction of5-cyanouracil with POCl₃ and N,N-dimethylaniline gave2,4-dichloro-5-cyanopyrimidine. ¹H NMR (CD₃OD): δ9.07; LCMS: ret. time:16.98 min. (fast method); purity: 70%. 7.1.52-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine(R926087) The reaction flask equipped with a magnetic stirring bar and arubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N₂inlet was charged with 3,4-ethylenedioxyaniline (34 g, 225 mmol), MeOH(100 mL), H₂O (300 mL) and 2,4-dichloro-5-fluoropyrimidine (25 g, 150mmol). The reaction mixture was stirred at room temperature for 1 h,diluted with H₂O (1.5 liter), acidified with 2N HCl (200 mL) andsonicated. The solid obtained was filtered, washed with H₂O and dried toobtain 33 g (78%) of the desired product,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine(R926087). ¹H NMR (CDCl₃): δ8.02 (1H, d, J=3Hz), 7.25 (d, 1H, J=1.2 Hz),6.98 (dd, 1H, J=2.4 and 8.1 Hz), 6.85 (d, 1H, J=5.7 Hz), 4.27 (m, 4H);¹⁹F NMR (CDCl₃): - 44570; LCMS: ret. time: 26.70 min.; purity 100%; MS(m/e): 283 (MH⁺). 7.1.62-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-nitro-4-pyrimidineamine(R940094) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-nitropyrimidine and 3,4-ethylenedioxyaniline were reactedto prepare2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-nitro-4-pyrimidineamine. LCMS:ret. time: 28.79 min.; purity: 90%; MS (m/e): 308 (M⁺); ¹HNMR (CDCl₃):δ10.07 (1H, s), 9.15 (1H, s), 7.02-6.88 (3H, m), 4.29 (4H, s). 7.1.72-Chloro-N4-(3-hydroxyphenyl)-5-nitro-4-pyrimidineamine (R940097) Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-nitropyrimidine and 3-hydroxyaniline were reacted toprepare 2-chloro-N4-(3-hydroxyphenyl)-5-nitro-4-pyrimidineamine. LCMS:ret. time: 24.21 min.; purity: 93%; MS (m/e): 267 (MH⁺); ¹HNMR (CDCl₃):δ10.20 (1H, s), 9.19 (1H, s), 7.32 (1H, t, J=2.2 Hz), 7.28 (1H, d, J=7.8Hz), 7.11 (1H, dd, J=7.8 and 1.8 Hz), 7.76 (1H, dd, J=8.4 and 2.4 Hz),5.20 (1H, s). 7.1.82-Chloro-N4-(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine (R926111) Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-hydroxyaniline were reacted toprepare product2-chloro-N4-(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CD₃OD): δ8.06 (bd, 1H), 7.26 (bd, 1H), 7.20-7.00 (m, 2H), 6,57 (d, 1H,J=7.2 Hz); ¹⁹F NMR (CD₃OD): - 44374; LCMS: ret. time: 22.02; purity:100%, MS (m/e): 240 (M⁺). 7.1.92-Chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine (R926073)In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3,4-dimethoxyaniline were reacted toprepare 2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine.¹HNMR (CDCl₃): δ8.02 (d, 1H, J=2.7 Hz), 7.38 (d, 1H, J=2.4 Hz), 7.05 (dd,1H, J=2.4 and 9.0 Hz), 6.89 (bs, 1H), 6.88 (d, 1H, J=9 Hz), 3.91 (s,3H), 3.89 (s, 3H); ¹⁹F NMR (CDCl₃): - 44593; LCMS: ret. time: 24.95min.; purity: 98%; MS (m/e): 285 (MH⁺). 7.1.102-Chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine (R926066) Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-ethoxyaniline were reacted toprepare 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR(CDCl₃): δ8.01 (d, 1H, J=3Hz), 7.49 (bdd, 2H, J=8.7 Hz), 6.92 (bdd, 2H,J=9.6 Hz), 4.03 (q, 2H, J=7.2 Hz), 1.42 (t, 3H, J=7.2 Hz); ¹⁹F NMR(CDCl₃): - 44627; LCMS: ret. time: 29.50 min.; purity: 99%, MS (m/e):268 (MH⁺). 7.1.112-Chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine (R926207) Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-chloroaniline were reacted toprepare 2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine.¹H NMR(CDCl₃): δ8.1 (bs, 1H), 8.60 (bdd, 2H), 8.36 (bdd, 2H), 6.90 (bs, 1H);¹⁹F NMR (CDCl₃): - 44407; LCMS: ret. time: 31.63 min.; purity: 85%; MS(m/e): 258 (MH⁺). 7.1.122-Chloro-5-fluoro-N4-(3-hydroxy-4-methoxycarbonylmethyleneoxyphenyl)-4-pyrimidineamine(R926393) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-hydroxy-4-methoxycarbonylmethylenoxyaniline were reacted to prepare2-chloro-5-fluoro-N4-(3-hydroxy-4-methoxycarbonylmethyleneoxyphenyl)-4-pyrimidineamine.¹HNMR (CD₃OD): δ8.03 (d, 1H, J=3.6 Hz), 7.35 (dd, 1H, J=2.4 Hz), 7.12 (dd,1H, J=2.4 and 8.7 Hz), 6.82 (d, 1H, J=8.1 Hz), 4.86 (s, 2H), 3.81 (s,3H). 7.1.13N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(R926573) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and tert-butyl 4-aminophenoxyacetatewere reacted to prepare productN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.02 (d, 1H, J=2.7 Hz), 7.51 (d, 1H, J=8.7 Hz), 6.93(d, 1H, J=8.7 Hz), 4.52 (s, 2H)), 1.49 (s, 9H); LCMS: ret. time: 29.50min.; purity: 97%; MS (m/e): 354 (MH⁺). 7.1.142-Chloro-5-fluoro-N4-(indol-5-yl)-4-pyrimidineamine (R926581) In likemanner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-aminoindole were reacted toprepare 2-chloro-5-fluoro-N4-(indol-5-yl)-4-pyrimidineamine. ¹H NMR(CDCl₃ + CD₃OD): δ9.45 (bs, 1H), 8.00 (bs, 1H), 7.82 (bd, 1H), 7.75 (s,1H), 7.38-7.10 (m, 3H), 6.40 (bs, 1H); LCMS: ret. time: 23.85 min.;purity: 100%; MS (m/e): 263 (MH⁺). 7.1.152-Chloro-5-fluoro-N4-(4-methoxymethyl-coumarin-7-yl)-4-pyrimidineamine(R926618) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-methoxymethyl-7-aminocoumarin werereacted to prepare2-chloro-5-fluoro-N4-(4-methoxymethyl-coumarin-7-yl)-4-pyrimidineamine.¹HNMR (CD₃OD): δ8.05 (d, 1H), 7.90 (s, 1H), 7.70 (dd, 1H, J=2.4 and 8.7Hz), 7.53 (d, 1H, J=8.7 Hz), 6.42 (s, 1H), 4.61 (s, 2H), 3.49 (s, 3H);LCMS: ret. time: 26.38 min.; purity: 87%; MS (m/e): 336 (MH⁺). 7.1.162-Chloro-N4-(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine(R926619) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 2,5-dimethyl-4-hydroxyaniline werereacted to prepare2-chloro-N4-(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 23.31 min.; purity: 96%; MS (m/e): 268 (MH⁺). 7.1.172-Chloro-N4-(5-chloropyrid-2-yl)-5-fluoro-4-pyrimidineamine (R926061) Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-chloro-2-aminopyridine werereacted to prepare2-chloro-N4-(5-chloropyrid-2-yl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CDCl₃): δ8.40 (d, 1H, J=8.7 Hz), 8.28 (d, 1H, J=1.8 Hz), 8.17 (d, 1H,J=2.1 and 9 Hz); LCMS: ret. time: 28.58 min.; purity: 100%; MS (m/e):259 (MH⁺). 7.1.182-Chloro-5-fluoro-N4-(5-methylpyrid-2-yl))-4-pyrimidineamine (R926062)In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-methyl-2-aminopyridine werereacted to prepare2-chloro-5-fluoro-N4-(5-methylpyrid-2-yl)-5-4-pyrimidineamine. ¹H NMR(CDCl₃): δ9.20 (s, 1H), 8.51 (s, 1H), 7.63 (d, 1H, J=5.7 Hz), 7.45 (dd,1H, J=1.8 and 9.3 Hz), 2.43 (s, 3H); LCMS: ret. time: 21.29 min.;purity: 97%; MS (m/e): 239 (MH⁺). 7.1.19N4-[6-(1,4-Benzoxazinyl)]-N2-chloro-5-fluoro-4-pyrimidineamine In likemanner to2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-1,4-benzoxazine were reacted(in methanol or methanol:water) to yieldN4-[6-(1,4-benzoxazinyl)]-N2-chloro-5-fluoro-4-pyrimidineamine. ¹H NMR(DMSO-d₆): δ8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m,1H), 4.05(m, 2H), 3.2 (m, 2H); LCMS: ret. time: 20.8 min.; purity: 95 %; MS(m/e): 295 (MH⁺). 7.1.20N2-Chloro-N4-(2,3-dihydrobenzofuran-5-yl)-5-fluoro-4-pyrimidinediamineIn like manner to2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-2,3-dihydrobenzofuran werereacted to yieldN2-chloro-N4-(2,3-dihydrobenzofuran-5-yl)-5-fluoro-4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.09 (d, 1H), 8.00 (m, 1H), 7.42 (m, 2H), 7.05 (m,1H), 4.53 (m, 2H), 4.25 (s, 2H), 3.15 (m, 2H); LCMS: ret. time: 20.35min.; purity: 90 %; MS (m/e): 266 (MH⁺). 7.1.212-Chloro-N4-(2-carboxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine(R940050) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 2-carboxy-4-chloroaniline werereacted to prepare2-chloro-N4-(2-carboxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine. LCMS:ret. time: 20.83 min.; purity: 98%; ¹H NMR (CDCl₃): δ8.64 (1H, d, J=4.8Hz), 8.24 (1H, d, J=2.7 Hz), 7.76 (1H, dd, J=8.7 and 2.7 Hz), 7.70 (1H,dd, J=8.7 and J=0.9 Hz). 7.1.22N-(2-Chloro-5-fluoro-4-pyrimidinyl)-L-tyrosine Methyl Ester (R940108) Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and L-tyrosine methyl ester were reactedto prepare N-(2-chloro-5-fluoro-4-pyrimidinyl)-L-tyrosine Methyl Ester.LCMS: ret. time: 23.32 min.; purity: 83%; MS (m/e): 325 (M+); ¹H NMR(CDCl₃): δ7.90 (1H, d, J=2.7 Hz), 6.95 (2H, d, J=8.7 Hz), 6.75 (2H, d,J=8.7 Hz), 5.95 (1H, s), 5.72 (1H, d, J=7.5 Hz), 5.05 (1H, dt, J=7.5 and5.3 Hz), 3.77 (3H, s), 3.16 (2H, m). 7.1.232-Chloro-N4-[3-(5-cyano-2-methyl-4-thiomethyl-6-pyrimidinyl)phenyl]-5-fluoro-4-pyrimidineamine(R940141) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-(5-cyano-2-methyl-4-thiomethyl-6-pyrimidinyl)aniline were reacted toprepare2-chloro-N4-[3-(5-cyano-2-methyl-4-thiomethyl-6-pyrimidinyl)phenyl]-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 18.23 min.; purity: 84%; MS (m/e): 386 (M⁺); ¹H NMR(CDCl₃): δ8.19 (1H, t, J=1.9 Hz), 8.11 (1H, d, J=3.1 Hz), 7.98 (1H, dd,J=8.1 and J=2.4 Hz), 7.82 (1H, dd, J=7.8 and 1.8 Hz), 7.57 (1H, t, J=7.8Hz), 7.11 (1H, s), 2.79 (3H, s), 2.69 (3H, s). 7.1.24N4-[4-(N-Benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(R945154) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,4-(N-benzylpiperazino)aniline and 2,4-dichloro-5-fluoropyrimidine gaveN4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ2.81 (m, 4 H), 3.37 (m, 6 H), 6.85 (br, 1 H), 6.93 (d,J=9.0 Hz, 2 H), 7.40 (m, 5 H), 7.50 (d, J=9.3 Hz, 2 H), 8.02 (d, J=2.7Hz, 1 H); LCMS: ret. time: 20.56 min, purity: 97.75%; MS (m/e): 398.00(MH⁺). 7.1.252-Chloro-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-4-pyrimidineamine(R945069) In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(178 mg, 0.6 mmol), trifluoroacetic anhydride (0.17 mL, 1.2 mmol) andpyridine (0.15 mL, 1.84 mmol) gave2-chloro-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-4-pyrimidineamine (110mg, 66%). ¹H NMR (acetone-d ₆): δ5.22 (s, 2 H), 7.24 (d, J=9.3 Hz, 2 H),7.62 (d, J=9.0 Hz, 2 H), 8.94 (d, J=1.8 Hz, 1 H); ¹⁹F NMR (acetone-d ₆):-137.60; LCMS: ret. time: 26.19 min.; purity: 89.93%; MS (m/e): 279.06(MH⁺). 7.1.26 N4-(4-Acetoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(R940210) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-acetoxyaniline were reacted toprepare N4-(4-acetoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine. LCMS:ret. time: 25.97 min.; purity: 98%; MS (m/e): 281 (M⁺); ¹H NMR (CDCl₃):δ8.07 (1H, d, J=2.7 Hz), 7.64 (2H, d, J=9 Hz), 7.12 (2H, d, J=9 Hz),7.00 (1H, s), 2.31 (3H, s). 7.1.272-Chloro-5-fluoro-N4-(4-hydroxyphenyl)-4-pyrimidineamine (R940211) Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-hydroxyaniline were reacted toprepare 2-chloro-5-fluoro-N4-(4-hydroxyphenyl)-4-pyrimidineamine. LCMS:ret. time: 20.10 min.; purity: 98%; MS (m/e): 240 (MH⁺); ¹H NMR (CDCl₃):δ8.02 (1H, d, J=2.7 Hz), 7.46 (2H, d, J=8.7 Hz), 6.86 (2H, d, J=9 Hz),6.85 (1H, s), 4.94 (1H, s). 7.1.282-Chloro-N4-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine(R940213) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 2,3-dimethyl-4-hydroxyaniline werereacted to prepare2-chloro-N4-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 23.29 min.; purity: 93%; MS (m/e): 268 (MH⁺); ¹H NMR(CDCl₃): δ8.00 (1H, d, J=2.7 Hz), 7.16 (1H, d, J=8.7 Hz), 6.68 (1H, d,J=8.7 Hz), 6.61 (1H, s), 4.87 (1H, s), 2.21 (3H, s), 2.16 (3H, s).7.1.292-Chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine(R940230) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-hydroxy-5-methylanilinewere reacted to prepare2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 26.26 min.; purity: 90%; ¹H NMR (DMSO-d₆): δ9.94 (1H,s), 9.21 (1H, s), 8.37 (1H, d, 3.6 Hz), 7.68 (1H, s), 7.41 (1H, s), 2.30(3H, s). 7.1.302-Chloro-5-fluoro-N4-[4-[3-(N-morpholino)propyl]oxyphenyl]-4-pyrimidineamine(R940247) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-[3-(N-morpholino)propyl]oxyanilinewere reacted to prepare2-chloro-5-fluoro-N4-[4-[3-(N-morpholino)propyl]oxyphenyl]-4-pyrimidineamine.LCMS: ret. time: 17.15 min.; purity: 99%; MS (m/e): 367 (MH⁺); ¹H NMR(CDCl₃): δ8.02 (1H, d, J=2.7 Hz), 7.49 (2H, d, J=8.7 Hz), 6.92 (2H, d,J=9 Hz), 6.85 (1H, s), 4.03 (2H, t, J=6.3 Hz), 3.73 (4H, t, J=4.6 Hz),2.53 (2H, t, J=6.7 Hz), 2.47 (4H, m), 1.98 (2H, m). 7.1.31N4-[2-[4-(N-Benzylpiperazino)ethyl]]-2-chloro-5-fluoro-4-pyrimidineamine(R940259) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine2,4-dichloro-5-fluoropyrimidine and 2-[4-(N-benzylpiperazino)ethylaminewere reacted to prepareN4-[2-[4-(N-benzylpiperazino)ethyl]]-2-chloro-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 21.11 min.; purity: 96%; MS (m/e): 349 (M⁺); ¹H NMR(CDCl₃): δ7.88 (1H, d, J=2.6 Hz), 7.31-7.17 (4H, m), 7.14 (1H, d, J=1.7Hz), 7.10 (1H, s), 3.76 (2H, m), 3.24 (2H, m), 2.90 (2H, m), 2.59 (2H,m), 2.34 (2H, m), 1.76 (4H, m). 7.1.32N4-(3-tert-Butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine (R940268) Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-tert-butylaniline were reacted toprepare N4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 33.96 min.; purity: 98 %; MS (m/e): 279 (M⁺); ¹H NMR(CDCl₃): δ8.05 (1H, d, J=3 Hz), 7.62 (1H, t, J=1.3 Hz), 7.50 (1H, m),7.34 (1H, t, J=7.8 Hz), 7.22 (1H, m), 6.96 (1H, sl), 1.34 (9H, s).7.1.33 2-Chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine(R925756) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-aminobenzylalcohol were reacted toyield 2-chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.45 (bs, 1H), 7.96 (d, 1H, J=2.9 Hz), 7.65 (d, 1H,J=8.2 Hz), 7.34 (s, 1H), 7.31 (t,1H, J=8.2 Hz), 7.07 (d, 1H, J=8.2),4.52 (s, 2H) ); ¹⁹F NMR (CDCl₃): -44394 (s, 1F); LCMS: ret. time: 20.29min.; purity: 100 %; MS (m/e): 254 (MH⁺). 7.1.342-Chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine(R925759) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-aminobenzylalcohol were reacted toyield 2-chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.08 (d, 1H, J=2.7 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.40(d, 2H, J=8.1 Hz), 6.99 (bs, 1H), 4.70 (s, 2H); ¹⁹F NMR (CDCl₃): -44570(s, 1F); LCMS: ret. time: 19.57 min.; purity: 99%; MS (m/e): 254 (MH⁺).7.1.352-Chloro-N4-(3,3-dihydroisobenzofuranynl-1-one-6-yl)-5-fluoro-4-pyrimidineamineR940279 In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-3,3-dihydroisobenzofuran-1-one were reacted to give2-chloro-N4-(3,3-dihydroisobenzofuranynl-1-one-6-yl)-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 21.15 min.; purity: 94.7 %; MS (m/e): 280 (MH⁺). 7.1.362-Chloro-5-fluoro-N4-((2R)-hydroxy-(1S)-methyl-2-phenylethyl)-4-pyrimidineamine(R925762) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and (1R,2S)-(−)-norephedrine werereacted to yield2-chloro-5-fluoro-N4-(2R-hydroxy-1S-methyl-2-phenylethyl)-4-pyrimidineamine.¹H NMR (CDCl₃): δ7.85 (d, 1H, J=3.0 Hz), 7.38 (m, 5H), 5.56 (d, 1H,J=7.5 Hz), 5.00 (d, 1H, J=3.0 Hz), 4.54 (m, 1H), 2.87 (bs, 1H), 1.10 (d,1H, J=6.9 Hz); ¹⁹F NMR (CDCl₃): - 44408. 7.1.37N-(2-Chloro-6-ethoxycarbonyl-5-nitro-4-pyrimidinyl)glycine Ethyl Ester(R925850) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and glycine ethyl esterhydrochloride salt were reacted to yieldN-(2-chloro-6-ethoxycarbonyl-5-nitro-4-pyrimidinyl)glycine Ethyl Ester.¹H NMR (CDCl₃): δ8.87 (bs, 1H), 4.48 (q, 2H, J=7.2 Hz), 4.39 (d, 2H,J=5.1 Hz), 1.40 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=7.2 Hz); LCMS: ret.time: 28.27 min.; purity: 97%; MS (m/e): 332 (M⁺). 7.1.382-Chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine(R925763) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 2-amino-1-phenylethanol were reactedto yield2-chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ7.88 (d, 1H, J=3.0 Hz), 7.41-7.32 (m, 5H), 5.71 (bs, 1H), 4.97(d, 1H, J=8.1 Hz), 3.98 (m, 1H), 3.56 (m, 1H), 2.57 (s, 1H); ¹⁹F NMR(CDCl₃): - 45149; LCMS: ret. time: 22.27 min.; purity: 98%; MS (m/e):263 (M⁺). 7.1.39 2-Chloro-5-fluoro-N4-(furfuryl)-4-pyrimidineamine(R925764) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and furfurylamine were reacted to yield2-chloro-5-fluoro-N4-(furfuryl)-4-pyrimidineamine. ¹H NMR (CDCl₃): δ7.91(d, 1H, J=1.8 Hz), 7.39 (d, 1H, J=1.2 Hz), 6.35 (m, 2H), 5.50 (bs, 1H),4.69 (d, 2H, J=5.1 Hz); ¹⁹F NMR (CDCl₃): - 45163; LCMS: ret. time: 24.52min.; purity: 97%; MS (m/e): 228 (M⁺). 7.1.40 R935010:(±)-2-Chloro-5-fluoro-N4-[1-(4-hydroxyphenyl)ethyl]-4-pyrimidineamine Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with1-(4-hydroxyphenyl)ethylamine to provide(±)-2-chloro-5-fluoro-N4-[1-(4-hydroxyphenyl)ethyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ7.88 (d, 1H, J=2.3 Hz), 7.50-7.47 (dd, 2H, J=1.7 and8.7 Hz), 7.26-7.23 (dd, J=8.7 and 1.7 Hz), 5.35-5.28 (m, 2H), 1.59 (d,3H, J=7.0 Hz). 7.1.41 R935011:(±)-N4-[1-(4-Bromophenyl)ethyl]-2-chloro-5-fluoro-4-pyrimidineamine Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with1-(4-bromophenyl)ethylamine to provide(±)-N4-[1-(4-bromophenyl)ethyl]-2-chloro-5-fluoro- 4-pyrimidineamine:¹HNMR (CDCl₃): δ7.88 (d, 1H, J=2.3 Hz), 7.49 (d, 2H, J=8.7 Hz), 7.25 (d,2H, J=8.7 Hz), 4.45-5.26 (m, 2H), 1.59 (d, 3H, J=7.0 Hz). 7.1.42R935007: 2-chloro-5-fluoro-N4-[1-[(1S)-phenyl]ethyl]-4-pyrimidineamineIn like manner to the preparation of of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 1-(1S)-phenyl ethylamine werereacted to produce2-chloro-5-fluoro-N4-[1-[(1S)-phenyl]ethyl]-4-pyrimidineamine. ¹H NMR(CDCl₃): δ7.86 (d, 1H, J =2.9 Hz), 7.37 (d, 4H, J =4.7 Hz), 7.34-7.30(m, 1H), 5.40-5.32 (m, 2H), 1.62 (d, 3H, J =6.4 Hz); LCMS: ret. time:29.5 min.; purity: 98%; MS (m/e): 252 (MH⁺). 7.1.43 R935008:2-Chloro-5-fluoro-N4-[1-[(1R)-pheny]lethyl]-4-pyrimidineamine In likemanner to the preparation of of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 1-(1R)-phenyl ethylamine werereacted to produce2-chloro-5-fluoro-N4-[1-[(1R)-phenyl]ethyl]-4-pyrimidineamine. ¹H NMR(CDCl₃): δ7.87 (d, 1H, J =2.9 Hz), 7.37 (d, 4H, J =4.1 Hz), 7.34-7.30(m, 1H), 5.38-5.31 (m, 2H), 1.62 (d, 3H, J =6.4 Hz). 7.1.44 R935012:2-Chloro-N4-[[di(3,5-di(trifluoromethyl)phenyl)]methyl]-5-fluoro-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted withdi[3,5-di(trifluoromethyl)phenyl]methylamine to provide2-chloro-N4-[[di(3,5-di(trifluoromethyl)phenyl)]methyl]-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.06 (d, 1H, J=2.3 Hz), 7.92 (s, 2H), 7.74 (s, 4H),6.75 (d, 1H, J=7.6 Hz), 5.80 (d, 1H, J=7.0 Hz). 7.1.45 R935014:2-Chloro-5-fluoro-N4-[1-[(1R)-4-methoxyphenyl]ethyl]-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with(R)-(+)-1-(4-methoxyphenyl)ethylamine to provide2-chloro-5-fluoro-N4-[1-[(1R)-4-methoxyphenyl]ethyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ7.84 (d, 1H, J=2.3 Hz), 7.30 (d, 2H, J=8.8 Hz), 6.89(d, 2H, J=8.8 Hz), 5.39-5.26 (m, 2H), 3.80 (s, 3H), 1.59 (d, 3H, J=6.4Hz). 7.1.46 R935015:2-Chloro-5-fluoro-N4-[1-[(1S)-4-methoxyphenyl]ethyl]-4-pyrimidineamineIn like manner to the preparation of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with(S)-(−)-1-(4-methoxyphenyl)ethylamine to provide2-chloro-5-fluoro-N4-[1-[(1S)-4-methoxyphenyl]ethyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ7.85 (d, 1H, J=2.3 Hz), 7.31 (d, 2H, J=8.8 Hz), 6.89(d, 2H, J=8.8 Hz), 5.38-5.29 (m, 2H), 3.80 (s, 3H), 1.59 (d, 3H, J=7.7Hz). 7.1.47 R935013:2-Chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine In like manner tothe preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro4-pyrimidineamine, 9-aminofluorene hydrochloride and2,4-dichloro-5-fluoropyrimidine with added diisopropylethylamine werereacted to produce 2-chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ7.97 (d, 1H, J=2.3 Hz), 7.73 (d, 2H, J=7.6 Hz), 7.59(d,2H, J=7.6 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.32 ( app t, 2H, J=7.6 Hz), 6.50(d, 1H, J=8.8 Hz), 5.45 (d, 1H, J=8.4 Hz). 7.1.48 R935210:2-Chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-4-pyrimidineamineIn like manner to the prepartation of2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,experiment, 2,4-dichloro-5-fluoropyrimidine was reacted with4-(methoxycarbonylmethyleneoxy)aniline to produce2-chloro-5-fluoro-N-[4-(methoxycarbonylmethyleneoxy)phenyl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ10.17 (s, 1H), 8.33 (d, 1H, J=3.5 Hz), 8.05 (s, 1H),7.91 (s, 1H), 7.74 (d, 1H, J=8.2 Hz), 7.40 (d, 1H, J=7.6 Hz), 5.31 (s,2H), 3.66 (s, 3H). 7.1.49 R935200:2-Chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine: Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-1-methyl-indazoline werereacted to provide2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine. ¹H NMR(DMSO-d₆): δ10.01 (s, 1H), 8.27 (d, 1H, J=3.5 Hz), 8.04 (d, 1H, J=1.7Hz), 7.98 (d, 1H, J=1.7 Hz), 7.64 (d, 1H, J=8.8 Hz), 7.56 (dd, 1H, J=1.7and 8.8 Hz), 4.02 (s, 3H). LCMS: ret. time: 21.72 min.; purity: 99%; MS(m/e): 278 (MH⁺). 7.1.50 R935017:N-(5-Bromo-2-chloropyrimidinyl)-4-fluorophenylethylamine In like mannerto the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro4-pyrimidineamine, 4-fluoro-α-methylbenzylamine and5-bromo-2,4-dichloropyrimidine were reacted to produceN-(5-bromo-2-chloropyrimidinyl)-4-fluorophenylethylamine. ¹H NMR(CDCl₃): δ8.12 (s, 1H), 7.35-7.25 (dd, 2H, J=3.5 and 8.7 Hz), 7.05 (t,1H, J=8.7 Hz), 5.63 (d, 1H, J=6.4 Hz), 5.36 (dq, 1H, 1H, J=6.4 and 7.0Hz), 1.60 (d, 3H, J=7.0 Hz); LCMS: ret. time: 30.73 min.; purity: 94%;MS (m/e): 331 (MH⁺). 7.1.51 R935009:(±)-N-(2-Chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine,4-fluoro-α-methylbenzylamine and 2,4-dichloro-5-fluoropyrimidine werereacted to produce(±)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine. ¹HNMR (CDCl₃): δ7.87 (d, 1H, J=2.3 Hz), 7.37-7.33 (dd, 2H, J=5.4 and 8.4Hz), 7.04 (t, 2H, J=8.4 Hz), 5.35-5.31 (m, 2H), 1.60 (d, 3H, J=6.4 Hz);LCMS: ret. time: 32.90 min.; purity: 98%; MS (m/e): 270 (MH⁺). 7.1.52R935022:5-Bromo-2-chloro-N4-[4-(N-methyl-2-methoxycarbonyl)ypyrrolyl)-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine,5-bromo-2,4-dichloropyrimidine andN-methyl-2-carbomethoxy-4-aminopyrrole hydrochloride with addeddiisopropylethylamine were reacted to produce the desired product5-bromo-2-chloro-N-(N-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.21 (s, 1H), 7.43 (d, 1H, J=1.8 Hz), 7.13 (br s, 1H),6.84 (d, 1H, J=1.8 Hz), 3.95 (s, 3H), 3.82 (s, 3H); LCMS: ret. time:26.96 min.; purity: 91%; MS (m/e): 346 (MH⁺). 7.1.53 R935234:2-Chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted toproduce2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ9.92 (s, 1H), 8.26 (d, 1H, J=3.5 Hz), 8.02-7.99 (m,2H), 7.60-7.56 (m, 5H), 7.11 (d, 2H, J=8.8 Hz), 5.58 (s, 2H); LCMS: ret.time: 32.09 min.; purity: 96%; MS (m/e): 398 (MH⁺). 7.1.54 R935235:2-Chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and5-(4-aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole were reacted toproduce2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ9.91 (s, 1H), 8.26 (d, 1H, J=3.5 Hz), 7.56 (d, 2H,J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz), 5.46 (s, 2H), 2.34 (s, 3H); LCMS:ret. time: 25.05 min.; purity: 98%; MS (m/e): 336 (MH⁺). 7.1.55 R935236:2-Chloro-5-fluoro-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethyleneioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and4-[1-ethoxycarbonyl-1-methyl)ethyl]aniline were reacted to produce2-chloro-5-fluoro-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ9.99 (s, 1H), 8.30 (d, 1H, J=3.5 Hz), 7.60 (d, 2H,J=8.8 Hz), 7.30 (d, 2H, J=8.8 Hz), 4.04 (qt, 2H, J=7.0 Hz), 1.47 (s,6H), 1.10 (t, 3H, J=7.0 Hz); LCMS: ret. time: 31.07 min.; purity: 97%;MS (m/e): 338 (MH⁺). 7.1.56 2,4-Dichloro-5-ethoxycarbonylpyrimidine Adry reaction flask equipped with a stirring bar and a reflux condenserwas charged with 5-ethoxycarbonyluracil (1.84 g, 10 mmol), POCl₃ (10 mL)and N,N-dimethylaniline (1 mL) and heated at 90° C. for 2 h. The excessPOCl₃ was removed under a reduced pressure and quenched with ice-water(100 g). The aqueous solution was extracted with ethyl ether (3 × 100mL), washed with saturated aqueous NaHCO₃ solution and water (100 mL,each). After drying over sodium sulfate, the ethyl ether was removed andthe residue was dried under a high vacuum to afford2,4-dichloro-5-ethoxycarbonylpyrimidine.¹H NMR (CDCl₃): δ9.00 (s, 1H),4.45 (q, 2H, J=6.9 Hz), 1.42 (t, 3H, J=6.9 Hz). 7.1.57N-(2-Chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester(R926518) andN-(4-Chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-phenylalanine Ethyl Ester(R926519) A mixture of L-phenylalanine Ethyl Ester Hydrochloride (0.137g, 0.6 mmol) 2,4-dichloro5-ethoxycarbonylpyrimidine (0.112 g, 0.5 mmol),triethylamine (0.7 mL, 0.6 mmol) in THF (4 mL) in a sealed tube washeated at 100° C. for 3 h. The reaction was diluted with H₂O (20 ML),extracted with CH₂Cl₂ (3 × 50 mL), washed with 2N HCl (10 mL), water (10mL) and solvent was evaporated. The residue obtained was purified bypreparative TLC using 15% EtOAc in hexanes to obtain two productsmainly, N-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanineEthyl Ester (R926518). ¹H NMR (CDCl₃): δ8.72 (d, 1H, J=6.92 Hz), 8.66(s, 1H), 7.32-7.17 (m, 5H), 5.05 (dq, 1H, J=1.2 and 5.7 Hz), 4.34 (q,2H, J=6.9 Hz), 4.20 (q, 2H, J=5.1 Hz), 3.24 (dd, 1H, J=5.4 Hz), 3.16(dd, 1H, J=7.5 Hz), 1.35 (t, 3H, J=7.2 Hz), 1.24 (t, 3H, J=7.2 Hz);LCMS: ret. time: 37.15 min.; purity: 99%; MS (m/e): 378 (MH⁺) andN-(4-chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-phenylalanine Ethyl Ester(R926519). ¹H NMR (CDCl₃): δ8.83 (s, 1H), 7.28 (m, 3H), 7.18 (m, 2H),6.00 (bt, 1H), 4.99 (bdq, 1H), 4.36 (q, 2H, J=7.8 Hz), 4.19 (q, 2H,J=6.9 Hz), 3.20 (t, 2H, J=6.9 Hz). 1.38 (t, 3H, J=4.5 Hz), 1.24 (t, 3H,J=6 Hz); LCMS: ret. time: 34.80 min.; purity: 88%; MS (m/e): 378 (M⁺).7.1.58 N-(2-Chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-valine Ethyl Ester(R926520) and N-(4-Chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-valine EthylEster (R926521) In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,2,4-dichloro-5-ethoxycarbonylpyrimidine and L-valine Ethyl Ester werereacted to prepare N-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-valineEthyl Ester (R926520). ¹H NMR (CDCl₃): δ8.80 (d, 1H, J=8.1 Hz), 8.68 (s,1H), 4.77 (dd, 1H, J=4.8 Hz), 4.36 (q, 2H, J=7.2 Hz), 4.24 (q, 2H, J=6.6Hz), 2.38 (m, 1H), 1.39 (t, 3H, J=6.9 Hz), 1.29 (t, 3H, J=7.2 Hz), 1.03(d, 3H, J=3 Hz), 1.00 (d, 3H, J=2.7 Hz); LCMS: ret. time: 36.54 min.;purity: 89%; MS (m/e): 330 (MH⁺) andN-(4-chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-valine Ethyl Ester(R926521). ¹H NMR (CDCl₃): δ8.82 (s, 1H), 6.02 (m, 1H), 4.69 (dd, 1H,J=4.8 and 4.5 Hz), 4.33 (q, 2H, J=7.5 Hz), 4.23 (q, 2H, J=7.5 Hz), 2.28(sept, 1H). 1.34 (t, 3H, J=6.9 Hz), 1.28 (t, 3H, J=7 Hz), 1.00 (d, 6H,J=7.2 Hz); LCMS: ret. time: 33.53 min.; purity: 91%; MS (m/e): 330 (M⁺).7.1.59 N-(2-Chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-leucine Ethyl Ester(R926522) In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,2,4-dichloro-5-ethoxycarbonylpyrimidine and L-leucine Ethyl Ester werereacted to prepare N-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-leucineEthyl Ester. ¹H NMR (CDCl₃): δ8.69 (s, 1H), 8.64 (d, 1H, 7.8 Hz), 4.84(s, 1H), 4.38 (q, 2H, J=7.2 Hz), 3.75 (s, 3H), 1.73 (m, 2H), 1.39 (t,3H, J=6.9 Hz), 0.97 (d, 3H, J=4.2 Hz), 0.95 (d, 3H, J=4.8 Hz) ; LCMS:ret. time: 36.09 min.; purity: 92%; MS (m/e): 330 (MH⁺). 7.1.60N-(2-Chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-alanine Ethyl Ester(R926523) and N-(4-Chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-alanineEthyl Ester (R926524) In like manner to the preparation ofN-(2-chloro-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,2,4-dichloro-5-ethoxycarbonylpyrimidine and L-valine Ethyl Ester werereacted to prepare N-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-alanineEthyl Ester(R926523). ¹H NMR (CDCl₃): δ8.80 (bd, 1H), 8.68 (s, 1H), 4.79(q, 1H, J=7.2 Hz), 4.35 (q, 2H, J=7.2 Hz), 4.24 (m, 2H), 1.53 (d, 3H,J=7.2 Hz), 1.38 (t, 3H, J=7.2 Hz), 1.29 (t, 3H, J=7.2 Hz); LCMS: ret.time: 31.89 min.; purity: 94%; MS (m/e): 303 (MH⁺) andN-(4-chloro-5-ethoxycarbonyl-2-pyrimidinyl)-L-alanine EthylEster(R926524). ¹H NMR (CDCl₃): δ8.80 (s, 1H), 6.01 (bs, 1H), 4.65 (bq,1H), 4.35 (q, 2H), 4.20 (q, 2H), 1.55, t, 3H), 1.40 (t, 3H), 1.25 (t,3H); LCMS: ret. time: 28.78 min.; purity: 84%; MS (m/e): 302 (M⁺).7.1.61 2-Chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine To asolution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 3.0 mmol) and4-n-butoxyaniline (0.49 g, 3 mmol) in acetone/H₂O (1:9 mL) at roomtemperature was added concentrated HCl (0.1 mL). The mixture was heatedat reflux for 1 h, cooled to room temperature, and made basic with 2 NNaOH (2 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL) andthe combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude black solid was purified bychromatography (4:1 hexanes/EtOAc) to afford2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.71 g,80%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ8.01 (d, J =2.7 Hz, 1H),7.51-7.46 (m, 2H), 6.95-6.89 (m, 2H), 6.83 (bs, 1H), 3.99-3.95 (t, J=6.5 Hz, 2H), 1.82-1.57 (m, 2H), 1.53-1.43 (m, 2H), 0.98 (t, J =7.2 Hz,3H). 7.1.62 2-Chloro-N4-(4-n-hexyloxyphenyl)-5-fluoro-4-pyridineamine Inlike manner to the preparartion of2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine, thereaction of 2,4-dichloro-5-fluoropyrimidine with 4-n-hexyloxyanilinegave 2-chloro-N4-(4-n-hexyloxyphenyl)-5-fluoro-4-pyridineamine. Thecrude product was purified by chromatography (4:1 CHCl₃/EtOAc) to afford(14) (0.74 g, 76%) as a red-brown oil that solidified upon standing: ¹HNMR (300 MHz, CDCl₃) δ8.01 (d, J =2.7 Hz, 1H), 7.50 (d, J =9.0 Hz, 2H),6.92 (d, J =9.0 Hz, 2H), 6.84 (bs, 1H), 3.96 (t, J =6.5 Hz, 2H),1.83-1.74 (m, 2H), 1.48-1.41 (m, 2H), 1.36-1.34 (m, 4H), 0.93-0.89 (m,3H). 7.1.63 N4-(3-Benzyloxyphenyl)-2-chloro-4-pyrimidineamine A mixtureof 2,6-dichloropyrimidine (2.00 g, 13.4 mmol), 3-benzyloxoaniline (2.07g, 13.4 mmol) and triethylamine (2.72 g, 26.8 mmol) in 1-butanol (20 mL)was stirred at 50° C. for 17 h. The reaction mixture was concentrated toremove most of the 1-butanol, the crude product was preadsorbed ontosilica gel using chloroform and purified by flash chromatography (95:5chloroform/ methanol) to affordN4-(3-benzyloxyphenyl)-2-chloro-4-pyrimidineamine (1.70 g, 40%) ascolorless oil: ¹H NMR (300 MHz, DMSO-d6) δ10.2 (s, 1H), 8.16 (d, J =6.0Hz, 1H), 7.48-7.24 (m, 7H), 7.12 (d, J =9.0 Hz, 1H), 6.78 (m, 2H), 5.11(s, 2H); ESI MS m/z 312 [C₁₇H₁₄ClN₃O + H]⁺. 7.1.64N4-[4-(tert-Butoxycarbonylmethyleneoxy)phenyl]-3-chloro-5-ethoxycarbonyl-4-pyrimidineamine(R926578) In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,5-carboxyethoxy-2,4-dichloropyrimidine and tert-butyl4-aminophenoxyacetatewere reacted to prepareN4-[4-(tert-butoxycarbonylmethyleneoxy)phenyl]-2-chloro-5-ethoxycarbonyl-2-chloro-4-pyrimidineamine.LCMS: MS (m/e): 407 (MH⁺). 7.1.65N4-(4-Ethoxyphenyl)-5-ethoxycarbonyl-2-trifluoromethyl-4-pyrimidineamine(R926059) In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,4-chloro-5-ethoxycarbonyl-2-trifluoromethylpyrimidine and4-ethoxyaniline were reacted to prepareN4-(4-ethoxyphenyl)-5-ethoxycarbonyl-2-trifluoromethyl-4-pyrimidineamine.¹H NMR (CDCl₃): δ10.39 (s, 1H), 9.02 (s, 1H), 7.59 (dd, 2H, J=2.1 and7.2 Hz), 6.91 (dd, 2H, J=1.8 and 6.6 Hz), 4.44 (q, 2H, J=7.5 Hz), 4.06(q, 2H, J=7.2 Hz), 1.44 (m, 6H); LCMS: ret. time: 38.49 min.; purity:100%; MS (m/e): 356 (MH⁺). 7.1.66N2-(4-Ethoxyphenyl)-5-methoxycarbonyl-4-trifluoromethyl-2-pyrimidineamine(R926060) In like manner to the preparation ofN-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester,2-chloro-5-methoxycarbonyl-4-trifluoromethylpyrimidine and4-ethoxyaniline were reacted to prepareN2-(2-ethoxyphenyl)-5-methoxycarbonyl-4-trifluoromethyl-2-pyrimidineamine.¹H NMR (CDCl₃): δ8.98 (s, 1H), 7.47 (m, 3H), 6.91 (dd, 2H, J=2.1 and 6.9Hz), 4.05 (q, 2H, 6.9 Hz), 1.42 (t, 3H, J=6.8 Hz); ¹⁹F NMR (CDCl₃):-19105; LCMS: ret. time: 33.87 min; purity: 100%; MS (m/e): 342 (MH⁺).7.1.672-Chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine(R926853) A reaction mixture containing2,4-dichloro-5-fluoro-pyrimindine (1.2 equivalents) and3-(tetrazol-5-yl)aniline (1 equivalents) in methanol:water (1:1; v/v)was heated at 60° C. for 24 h. Upon dilution with water andacidification, the solid formed was fitered, washed with water, driedand analyzed to give2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine(R926853). Alternatively this reaction can be achieved by treating2,4-dichloro-5-fluoropyrimidine (1 equivalent) with3-(tetrazol-5-yl)aniline (3 equivalents) in methanol:water (1:1; v/v) at60° C. for 2-3 hours or at room temperature for 24 h to give2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. ¹HNMR (DMSO-d₆): δ10.25 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H, J=3.6 Hz),7.90 (dd, 1H, J=0.9 and 9 Hz), 7.75 (d, 1H, J=7.5 Hz), 7.61 (t, 1H,J=7.8 Hz); LCMS: purity: 90%; MS (m/e): 292 (MH⁺). 7.1.682-Chloro-N4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine(R926858) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with2,5-dimethoxy-4-chloroaniline gave2-chloro-N4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine.LCMS: purity: 97%; MS (m/e): 316 (M-2H) and 320 (M+2H). 7.1.692-Chloro-5-fluoro-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4-pyrimidineamine(R926861) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-methoxycarbonyl-5-trifluoromethylaniline gave2-chloro-5-fluoro-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4-pyrimidineamine.¹H NMR (CD₃OD): δ8.60 (s, 1H), 8.43 (s, 1H), 8.20 (d, 1H, J=3 Hz), 7.99(s, 1H), 3.96 (s, 3H); ¹⁹F NMR (CD₃OD): -18332, - 18374; and - 44259;LCMS: purity: 91%; MS (m/e): 350 (MH⁺). 7.1.702-Chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl)-4-pyrimidineamine(R926869) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-(2-phenyl-1,3,4-oxadiazol-5-yl)aniline gave2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl)-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ10.28 (s, 1H), 8.62 (s, 1H), 8.39 (d, 1H, J=3.3 Hz),8.11 (m, 2H), 7.98 (bd, 1H, J=6.9 Hz), 7.88 (bd, 1H, J=8.4 Hz), 7.65 (m,4H); LCMS: purity: 76%; MS (m/e): 76%. 7.1.712-Chloro-N4-[3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl)-5-fluoro-4-pyrimidineamine(R926873) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)aniline gave2-chloro-N4-[3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-4-pyrimidineamine.¹H NMR (CD₃OD): δ8.42 (t, 1H, J=1.8 Hz), 8.19 (d, 1H, J=3.3 Hz), 7.99(dt, 1H, J=1.2 and 8.1 Hz), 7.82 (dt, 1H, J=1.2 and 8.1 Hz), 7.58 (t,1H, J=9 Hz), 4.24 (q, 2H, J=3.9 Hz), 4.17 (s, 2H), 1.28 (t, 3H, J=7.2Hz); LCMS: purity: 85%; MS (m/e): 379 (MH⁺). 7.1.722-Chloro-5-fluoro-N4-(4-trifluoromethoxyphenyl)-4-pyrimidineamine(R926875) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with4-trifluoromethoxyaniline gave2-chloro-5-fluoro-N4-(4-trifluoromethoxyphenyl)-4-pyrimidineamine. ¹HNMR (CDCl₃): δ8.11 (d, 1H, J=2.1 Hz), 7.68 (dd, 2H, J=2.4 and 7.6 Hz),7.26 (dd, 2H, J=3 and 8.7 Hz), 7.0 (bs, 1H); ¹⁹F NMR (CD₃OD): δ-16517and -44523; LCMS: purity: 94%; MS (m/e): 308 (MH⁺). 7.1.732-Chloro-5-fluoro-N4-(4-trifluoromethylphenyl)-4-pyrimidineamine(R926876) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with4-trifluoromethylaniline gave2-chloro-5-fluoro-N4-(4-trifluoromethylphenyl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ8.15 (d, 2.1 Hz), 7.80 (d, 2H, J=7.1 Hz), 7.66 (d, 2H, J=9Hz), 7.10 (bs, 1H); ¹⁹F NMR (CDCl₃): -17682 and - 44362; LCMS: purity:91% and MS (m/z): 292 (MH⁺). 7.1.742-Chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineamine(R926877) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with4-chloro-3-trifluoromethylaniline gave2-chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.15 (d, 1H, J=2.1 Hz), 7.96 (d, 1H, J=3 Hz), 7.91 (dd,1H, J=2.7 Hz and 8.7 Hz), 7.53 (d, 1H, J=8.1 Hz), 7.06 (bs, 1H); ¹⁹F NMR(CDCl₃): - 17892 and - 44402; LCMS: purity: 93%; MS (m/e): 326 (M⁺).7.1.75 2-Chloro-5-fluoro-N4-(6-methoxypyridin-3-yl)-4-pyrimidineamine(R926878) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-amino-6-methoxypyridine gave2-chloro-5-fluoro-N4-(6-methoxypyridin-3-yl)-4-pyrimidineamine. ¹H NMR(CD₃OD): δ8.39 (d, 1H, J=3.0 Hz), 8.10 (d, 1H, J=3.6 Hz), 7.95 (dd, 1H,J=2.4 and 9 Hz), 8.30 (d, 1H, J=9 Hz), 3.91 (s, 3H); ¹⁹F NMR (CD₃OD): -44737; LCMS: purity: 97%; MS (m/e): 255 (M⁺). 7.1.762-Chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine (R926882) Inlike manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-difluoroanilinegave 2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CDCl₃): δ8.10 (d, 1H, J=2.1 Hz), 7.72 (m, 1H), 7.22 (m, 2H), 6.95 (bs,1H); LCMS: purity: 93%; MS (m/e): 260 (M⁺). 7.1.772-Chloro-N4-(3,4-Dichlorophenyl)-5-fluoro-4-pyrimidineamine (R926884) Inlike manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-dichloroanilinegave 2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine. LCMS:purity: 95%; MS (m/e): 294 (M+ 2H). 7.1.782-Chloro-5-fluoro-N4-(6-methylpyridin-2-yl)-4-pyrimidineamine (R926888)In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with2-amino-6-methylpyridine gave2-chloro-5-fluoro-N4-(6-methylpyridin-2-yl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ8.23 (s, 1H), 8.19 (s, 1H), 8.12 (d, 1H, J=3 Hz), 7.55 (bs,1H), 7.69 (t, 1H, J=7.4 Hz), 9.35 (d, 1H, J=7.5 Hz); ¹⁹F NMR (CDCl3): -44073; LCMS: purity: 96%; MS (m/e): 239 (M⁺). 7.1.792-Chloro-N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine(R926889) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-amino-2.6-dimethoxypyridine gave2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine. ¹HNMR (CDCl₃): δ8.57 (d, 1H, J=8.7 Hz), 8.02 (d, 1H, J=2.7 Hz), 6. 40 (d,1H, J=8.1 Hz), 4.03 (s, 3H), 3.98 (s, 3H); ¹⁹F NMR (CDCl₃): - 44640;LCMS: purity: 90%; MS (m/e): 285 (M⁺). 7.1.802-Chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine (R920400)In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-amino-6-chloropyridine gave2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine. ¹H NMR(CDCl₃): δ8.53 (d, 1H, J=3 Hz), 8.25 (dd, 1H, J=3 and 9 Hz), 8.15 (d,1H, J=2.4 Hz), 7.39 (d, 1H, J=8.7 Hz), 7.00 (bs, 1H); LCMS: purity: 98%;MS (m/e): 259 (M⁺). 7.1.812-Chloro-5-fluoro-N4-(4-methylpyridin-2-yl)-4-pyrimidineamine (R920401)In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with2-amino-4-methylpyridine gave2-chloro-5-fluoro-N4-(4-methylpyridin-2-yl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ8.22 (s, 1H), 8.16 (d, 1H, J=8.4 Hz), 8.13 (d, 1H, J=2.4 Hz),6.91 (d, 1H, J=5.4 Hz), 2.42 (s, 3H); LCMS: purity: 87%; MS (m/e): 239(MH⁺). 7.1.822-Chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine(R920402) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-trifluoromethoxyaniline gave2-chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine. ¹HNMR (CDCl₃): δ8.12 (d, 1H, J=3 Hz), 7.68 (bs, 1H), 7.53 (dd, 1H, J=1.2and 8.4 Hz), 7.41 9t, 1H, J=8.1 Hz), 7.04 (bdt, 2H); ¹⁹F NMR (CDCl₃):-16430 and - 44463; LCMS: purity: 89%; MS (m/e): 308 (MH⁺). 7.1.832-Chloro-N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine(R920403) In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3,4-difluoromethylenedioxyaniline gave2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.09 (d, 1H, J=3 Hz), 7.70 (d, 1H, J=2.4 Hz), 7.10 (dd,1H, J=2.4 and 8.7 Hz), 7.06 (t, 1H, J=8.1 Hz), 6.97 (bs, 1H); ¹⁹F NMR(CDCl₃): - 14175 and - 44562; LCMS: purity: 95%; MS (m/e): 304 (MH⁺).7.1.84 2-Chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine (R920409)In like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with 6-aminoquinoline gave2-chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine. ¹H NMR (CDCl₃):δ8.02 (dd, 1H, J=2.7 Hz), 8.00 (dd, 1H, J=2.4 Hz), 7.73 (d, 1H, J=9 Hz),7.68 (dd, 1H, J=2.4 and 8.7 Hz), 7.28 (t, 1H, J=10.5 Hz), 6.42 (d, 1H,J=9.3 Hz); ¹⁹F NMR (CDCl₃): - 44344; LCMS: purity: 91%; MS (m/e): 292(M⁺). 7.1.852-Chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamineIn like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with3-chloro-4-trifluoromethoxyaniline gave2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.15 (d, 1H, J=3.0 Hz), 7.86 (d, 1H, J=2.1 Hz), 7.61(dd, 1H, J=2.1 and 8.7 Hz), 7.35 (dd, 1H, J=1.2 and 8.7 Hz), 6.98 (bs,1H); LCMS: purity: 97%; MS (m/e): 342 (M+2H). 7.1.862-Chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine Inlike manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with4-chloro-3-methoxyaniline gave2-chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-aminopyrimidine. LCMS:purity: 88%; MS (m/e): 288 (MH⁺). 7.1.872-Chloro-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-4-pyrimidinediamineIn like manner to the preparation of2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine thereaction of 2,4-dichloro-5-fluoropyrimidine with5-amino-2-(2-hydroxyethyloxy)pyridine gave2-chloro-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.28 (d, 1H, J=2.4 Hz), 8.08 (m, 1H), 7.99 (m, 1H),7.00 (bs, 1H), 6.87 (bd, 1H), 4.47 (m, 2H), 3.97 (m, 2H). 7.1.882-Chloro-N4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-5-fluoro-4-pyrimidineamine(R926910) In a like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and7-amino-1,2,3,4-tetrahydroisoquinoline were reacted to provide2-chloro-N4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-5-fluoro-4-pyrimidineamine.¹HNMR (CDCl₃): δ8.08 (d, 1H, J=3.0 Hz), 7.95 (d, 1H, J=6.0 Hz), 7.50-7.42(m, 2H), 7.21 (d, 1H, J=8.4 Hz), 6.96-6.90 (m, 1H), 4.95 (s, 2H), 4.04(t, 2H, J=5.7 Hz), 2.99 (t, 2H, J=5.7 Hz); ¹⁹F NMR (282 MHz, CDCl₃):-42555, -44573; LCMS: purity: 98%; MS (m/e): 410(MH⁺). 7.1.892-Chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamine(R926911) In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and7-amino-2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline were reactedto provide2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.03 (s, 1H), 7.50-7.26 (m, 2H), 7.19-7.11 (m, 2H),4.57 (s, 2H), 3.64 (t, 2H, J=5.7 Hz), 2.80 (t, 2H, J=5.7 Hz), 1.48 (s,9H); LCMS: purity: 89%; MS (m/e): 379(M⁺). 7.1.902-Chloro-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-4-pyrimidineamine(R926912) A solution of2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineaminein 40% trifluoroacetic acid/dichloromethane was stirred at rt for 30min. Removal of the solvent left an oily residue which was suspended inwater, made basic with NaHCO₃, and extracted with ethyl acetate.Purification by column chromatography over silica gel provided2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.04 (d, 1H, J=3.0 Hz), 7.37 (dd, 1H, J=2.4 and 8.4Hz), 7.27 (d, 1H, J=1.5 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.92 (s, 1H), 4.04(s, 2H), 3.15 (t, 2H, J=6.0 Hz), 2.79 (t, 2H, J=6.0 Hz); ¹⁹F NMR (282MHz, CDCl₃): -44648; LCMS: purity: 97%; MS (m/e): 279(MH⁺). 7.1.912-Chloro-5-fluoro-N4-(4-methyl-3-trifluoromethylphenyl)-4-pyrimidineamine(R926920) In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-methyl-3-trifluoromethylanilinewere reacted to provide2-chloro-5-fluoro-N4-(4-methyl-3-trifluoromethylphenyl)-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.10 (d, 1H, J=3.0 Hz), 7.85-7.78 (m, 2H), 7.33 (d, 1H,J=9.3 Hz), 6.96 (bs, 1H), 2.48 (d, 3H, J=1.2 Hz); ¹⁹F NMR (282 MHz,CDCl₃): -17641, -44541; LCMS: purity: 97%; MS (m/e): 306(MH⁺). 7.1.922-Chloro-5-fluoro-N4-(4-fluoro-3-methylphenyl)-4-pyrimidineamine(R926921) In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-methylaniline werereacted to provide2-chloro-5-fluoro-N4-(4-fluoro-3-methylphenyl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ8.06 (d, 1H, J=2.4 Hz), 7.48-7.43 (m, 1H), 7.39 (dd, 1H, J=2.7and 6.3 Hz), 7.03 (t, 1H, J=9.0 Hz), 6.84 (bs, 1H), 2.30 (d, 1H, J=1.8Hz); ¹⁹F NMR (282 MHz, CDCl₃): -34285, -44676; LCMS: purity: 95%; MS(m/e): 257(MH⁺). 7.1.93N4-[3-[(N-t-butoxycarbonyl)aminomethyl]-4-methylphenyl]-2-chloro-5-fluoro-4-pyrimidineamine(R926924) In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-[(N-t-butoxycarbonyl)aminomethyl]-4-methylaniline were reacted toprovideN4-[3-[(N-t-butoxycarbonyl)aminomethyl]-4-methylphenyl]-2-chloro-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.05 (d, 1H, J=3.0 Hz), 7.52 (d, 1H, J=9.3 Hz), 7.45(s, 1H), 7.19 (d, 1H, J=8.1 Hz), 6.96-6.89 (m, 1H), 4.80 (bs, 1H), 2.31(s, 2H), 1.46 (s, 9H); LCMS: purity: 97%; MS (m/e): 311 (M - (t-butyl)⁺). 7.1.942-Chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]methyl]phenyl]-5-fluoro-4-pyrimidineamineIn a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and ethyl1-(3-aminobenzyl)piperidine-4-carboxylate were reacted to provide2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]methyl]phenyl]-5-fluoro-4-pyrimidineamine.LCMS: purity: 97%; MS (m/e): 394(MH⁺). 7.1.952-Chloro-N4-[3-[4-(ethoxycarbonyl)piperidinocarbonyl]phenyl]-5-fluoro-4-pyrimidineamine In a like manner to thepreparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-[[4-(ethoxycarbonyl)piperidino]carbonyl]aniline were reacted toprovide2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamine.LCMS: purity: 96%; MS (m/e): 407(M⁺). 7.1.962-Chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamineIn a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineaminewas reduced with Dibal-H to yield2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.05 (d, 1H, J=3.0 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.14(d, 1H, J=8.1 Hz), 6.93 (bs, 1H), 4.82-4.78 (m, 1H), 2.82-2.71 (m, 2H),2.08-1.74 (m, 5H) ; ¹⁹F NMR (282 MHz, CDCl₃): -44661; LCMS: purity: 94%;MS (m/e): 294(MH⁺). 7.1.972-Chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineamine.In a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-1-tetralone were reacted toprovide2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineamine.¹H NMR (DMSO-d ₆): δ10.08 (s, 1H), 8.31 (d, 1H, J=3.3 Hz), 8.15 (d, 1H,J=2.4 Hz), 7.82 (dd, 1H, J=2.4 and 8.1 Hz), 7.36 (d, 1H, J=8.1 Hz), 2.91(t, 2H, J=6.0 Hz), 2.59 (t, 2H, J=6.0 Hz), 2.07-1.98 (m, 2H); LCMS:purity: 93%; MS (m/e): 294(MH⁺). 7.1.982-Chloro-5-fluoro-N4-[3-(trifluoromethylthio)phenyl]-4-pyrimidineamineIn a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-(trifluoromethylthio)aniline werereacted to provide2-chloro-5-fluoro-N4-[3-(trifluoromethylthio)phenyl]-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.13 (bs, 1H), 7.92 (bs, 1H), 7.89-7.84 (m, 1H),7.48-7.45 (m, 2H), 7.04 (bs, 1H); LCMS: purity: 97%; MS (m/e): 325(MH⁺).7.1.992-Chloro-5-fluoro-N4-[(3-dihydroxyboryl)phenyl)]-4-pyrimidineamine In alike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-aminobenzeneboronic acid werereacted to provide2-chloro-5-fluoro-N4-[(3-dihydroxyboryl)phenyl)]-4-pyrimidineamine.7.1.100 2-Chloro-5-fluoro-N4-[(1H)-indol-6-yl]-4-pyrimidineamine In alike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted toprovide 2-chloro-5-fluoro-N4-[(1H)- indol-6-yl]-4-pyrimidineamine. LCMS:purity: 92%; MS (m/e): 263(MH⁺). 7.1.1012-Chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine In alike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methylaniline werereacted to provide2-chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine. LCMS:purity: 97%; MS (m/e): 255(MH⁺). 7.1.1022-Chloro-5-fluoro-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-4-pyrimidineamineIn a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-2-(methoxycarbonyl)-(1H)-indole were reacted to provide2-chloro-5-fluoro-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-4-pyrimidineaminewhich was used without further purification. LCMS: purity: 65%; MS(m/e): 322(MH⁺). 7.1.103N4-[3-(4-(2-Chloro-5-fluoropyrimidine)-N-aminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(R940298) The reaction flask equipped with a magnetic stirring bar and arubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N₂inlet was charged 3-aminobenzylamine (0.22 g, 1.79 mmol), MeOH (1 mL),H₂O (3 mL) and 2,4-dichloro-5-fluoropyrimidine (0.3 g, 1.79 mmol). Thereaction mixture was stirred at 80° C. for 30 min., cool to roomtemperature, diluted with H₂O (30 mL). Upon saturation with sodiumchloride it was extracted with ethyl acetate (3 × 20 mL), dried overanhydrous sodium sulfate and the solvent was removed. The resultingresidue was filtered through a pad of silica gel (200-400 mesh) using 1to 3% MeOH in CH₂Cl₂ to obtainN4-[3-(4-(2-chloro-5-fluoropyrimidine)-N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamineR940298.¹H NMR (DMSO-d₆): δ10.09 (1H, s), 8.88 (1H, t, J=5.85 Hz), 8.40 (1H, d,J=3.6 Hz), 8.23 (1H, d, J=3.3 Hz), 7.74 (1H, s), 7.70 (1H, d, J=8.1 Hz),7.44 (1H, t, J=7.8 Hz), 7.19 (1H, d, J=8.1 Hz), 4.69 (2H, d, J=5.7 Hz ;purity 92 %. 7.1.1042-Chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine(R940302) The reaction flask equipped with a magnetic stirring bar and arubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N₂inlet was charged with 3-methyloxycarbonyl-4-methoxyaniline (0.88 g,4.86 mmol), MeOH (3 mL), H₂O (7 mL) and 2,4-dichloro-5-fluoropyrimidine(0.81 g, 4.86 mmol). The reaction mixture was stirred at 60° C. for 30min., diluted with H₂O (50 mL), acidified with 2N HCl (6 mL) andsonicated. The solid obtained was filtered, washed with H₂O and dried toproduce2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamineR940302.¹H NMR (DMSO-d₆): δ10.10 (1H, s), 8.39 (1H, d, J=3.6 Hz), 8.04 (1H, d,J=2.7 Hz), 7.98-7.93 (1H, m), 7.30 (1H, d, J=9 Hz), 3.92 (3H, s), 3.89(3H, m) ; purity 96% ; MS (m/e): 312 (MH+). 7.1.1052-Chloro-5-fluoro-N4-(4-phahthlimide)-4-pyrimidineamine (R940303) Inlike manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-aminophthalimide were reacted toproduce 2-chloro-5-fluoro-N4-(4-phahthlimide)-4-pyrimidineamineR940303.¹H NMR (DMSO-d₆): δ11.38 (1H, s), 10.60 (1H, s), 8.57 (1H, d, J=3.3 Hz),8.39 (1H, d, J=1.8 Hz), 8.18 (1H, dd, J=8.4 Hz, J=2.1 Hz), 7.93 (1H, d,J=8.1 Hz) ; purity 90% ; MS (m/e): 293 (MH+). 7.1.1062-Chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-4-pyrimidineamine(R940305) In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-methylaminocarbonyl-4-methoxyaniline were reacted to produce2-chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-4-pyrimidineamineR940305.¹H NMR (DMSO-d₆): δ9.91 (1H, s), 8.31 (1H, d, J=3.6 Hz), 8.11 (1H, d,J=2.7 Hz), 7.78 (1H, dd, J=9 Hz, J=2.7 Hz), 7.59 (1H, m), 6.87 (1H, d,J=9 Hz), 3.90 (3H, s), 2.96 (3H, d, J=4.5 Hz) ; purity 93%. 7.1107.N2-Chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-4-pyrimidineamine(R940313) In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-(N-morpholinomethylene)-4-methoxyaniline were reacted to produce2-chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-4-pyrimidineamineR940313.¹H NMR (DMSO-d₆): δ10.00 (1H, s), 8.35 (1H, d, J=3.3 Hz), 7.72 (1H, d,J=3 Hz), 7.58 (1H, d, J=9.3 Hz), 7.12 (1H, d, J=8.4 Hz), 3.89 (3H, s),3.8-3.5 (6H, m), 2.58 (4H, m) ; purity 96% ; MS (m/e): 352 (M). 7.1.108N4-[3-(N-tert-Butoxycarbonyl-N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(R940315) In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-(N-tert-butoxycarbonyl-N-methylaminomethylene)-aniline were reacted toproduceN4-[3-(N-tert-butoxycarbonyl-N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamineR940315. ¹H NMR (DMSO-d₆): δ10.13 (1H, s), 8.42 (1H, d, J=3.6 Hz), 7.69(1H, m), 7.64 (1H, s), 7.45 (1H, t, J=7.6 Hz), 7.09 (1H, d, J=7.8 Hz),4.48 (2H, s), 2.90 (3H, s), 1.49 (9H, m) ; purity 92% ; MS (m/e): 367(MH+). 7.1.109N4-(3-(N-tert-Butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine (R940320) In like manner to thepreparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxy-anilinewere reacted to produceN4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamineR940320.¹H NMR (DMSO-d₆): δ10.01 (1H, s), 8.34 (1H, d, J=3.6 Hz), 7.52 (2H, m),7.08 (1H, d, J=8.7 Hz), 4.33 (3H, m), 3.90 (3H, s), 1.50-1.30 (9H, m),1.18 (6H, d, J=6.9 Hz) ; purity 95%. 7.1.1102-Chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamine(R940322) In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one were reacted to produce2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineR940322. ¹H NMR (DMSO-d₆): δ10.89 (1H, s), 10.04 (1H, s), 8.38 (1H, d,J=3.6 Hz), 7.35 (2H, m), 7.04 (1H, d, J=8.4 Hz), 1.50 (6H, s) ; purity91.4% ; MS (m/e): 322 (M). 7.1.1112-Chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-(pyridyl-1-oxide)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine(R940328) In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and2-(6-amino-3-dihydro-2,2-dimethyl-benzo[1,4]oxazin-4-yl)pyridine 1-Oxidewere reacted to produce2-chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-(pyridyl-1-oxide)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamineR940328. ¹H NMR (DMSO-d₆): δ9.82 (1H, s), 8.39 (1H, dd, J=6.3 Hz, J=1.2Hz), 8.30 (1H, d, J=3.6 Hz), 7.63 (1H, dd, J=8.4 Hz, J=2.4 Hz), 7.47(1H, td, J=7.5 Hz, J=1.8 Hz), 7.34 (1H, m), 7.21 (1H, dd, J=8.7 Hz,J=2.4 Hz), 7.07 (1H, d, J=2.7 Hz), 6.91 (1H, d, J=8.7 Hz), 3.64 (2H, s),1.41 (6H, s) ; purity 95.8% ; MS (m/e): 402 (MH+). 7.1.1122-Chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine(R940336) In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazine werereacted to produce2-chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamineR940336.¹H NMR (DMSO-d₆): δ9.95 (1H, s), 8.38 (1H, dd, J=4.8 Hz, J=1.8 Hz), 8.33(1H, d, J=3.6 Hz), 7.84 (1H, d, J=2.1 Hz), 7.79 (1H, ddd, J=15.6 Hz,J=7.2 Hz, J=2.1 Hz), 7.57 (1H, d, J=8.4 Hz), 7.19 (1H, dd, J=8.4 Hz,J=2.4 Hz), 7.01-6.95 (2H, m), 3.96 (2H, s), 1.32 (6H, s) ; purity 99.3%; MS (m/e): 386 (MH+). 7.1.1132-Chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamine(R940342) In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one were reacted to produce2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineR940342.¹H NMR (DMSO-d₆): δ12.24 (1H, s), 10.23 (1H, s), 8.45 (1H, dd, J=3.3 Hz,J=0.9 Hz), 7.66 (1H, dd, J=4.2 Hz, J=2.4 Hz), 7.55 (1H, dt, J=9 Hz,J=2.5 Hz), 7.43 (1H, d, J=9 Hz+); ¹⁹F NMR (DMSO-d₆): δ-21582, -43415 ;purity 96.2%; MS (m/e) : 331 (MH+). 7.1.1142-Chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-4-pyrimidineamine(R940344) In like manner to the preparation of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and7-amino-2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one were reacted toproduce2-chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-4-pyrimidineamineR940344.¹H NMR (DMSO-d₆): δ11.32 (1H, s), 10.20 (1H, s), 8.45 (1H, d, J=3.6 Hz),8.33 (1H, d, J=2.1 Hz), 7.84 (1H, d, J=2.1 Hz), 1.54 (6H, s) ; purity90.8% ; MS (m/e): 324 (MH+). 7.1.115N4-(4-Aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(R945028) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine (250 mg, 1.50 mmol) and4-aminocarbonylmethyleneoxyaniline (540 mg, 3.25 mmol) were reacted toyieldN4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine.LCMS: ret. time: 18.34 min.; purity: 100%; MS (m/e): 298.47 (MH⁺).7.1.1162-Chloro-5-fluoro-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-4-pyrimidineamine(R945298) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one were reacted to yield2-chloro-5-fluoro-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ4.63 (s, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 8.33 (d, J=3.3 Hz, 1H), 10.14 (s, 1H, NH), 11.19 (s, 1H, NH);¹⁹F NMR (282 MHz, DMSO-d₆): δ- 152.35; LCMS: ret. time: 26.74 min.;purity: 85.90%; MS (m/e): 296.13 (MH⁺). 7.1.117N4-(1,4-Benzoxazin-6-yl)-N2-chloro-5-fluoropyrimidineamine In likemanner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-1,4-benzoxazine were reactedto yield N4-(1,4-Benzoxazin-6-yl)-N2-chloro-5-fluoropyrimidineamine 1HDMSO 8.2 (d, 1H),6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m,1H), 4.05 (m, 2H),3.2 (m, 2H) purity 95 % MS (m/e): 281(MH⁺). 7.1.118N4-(1,4-Benzoxazin-7-yl)]-N2-chloro-5-fluoropyrimidineamine In likemanner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-1,4-benzoxazine were reactedto yield N4-(1,4-Benzoxazin-7-yl)]-N2-chloro-5-fluoropyrimidineamine 1HDMSO 8.2 (d, 1H),6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m,1H), 4.05 (m, 2H),3.2 (m, 2H) purity 94 % MS (m/e):281(MH⁺). 7.1.119N4-(1,4-Benzoxazin-3-on-6-yl)-N2-chloro-5-fluoropyrimidineamine In likemanner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-1,4-benzoxazine-3-one werereacted to yieldN4-(1,4-Benzoxazin-3-on-6-yl)-N2-chloro-5-fluoropyrimidineamine 1H DMSO8.2 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m,1H), 4.73 (s, 2H) purity96 % MS (m/e): 295 (MH⁺). 7.1.120N4-(1,4-Benzoxazin-3-on-7-yl)-N2-chloro-5-fluoropyrimidineamine In likemanner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-1,4-benzoxazine-3-one werereacted to yieldN4-(1,4-Benzoxazin-3-on-7-yl)-N2-chloro-5-fluoropyrimidineamine 1H DMSO8.2 (d, 1H),6.8 (m, 1H), 6.79 (m, 1H), 6.6 (m,1H), 4.68 (s, 2H) purity93 % MS (m/e): 295 (MH⁺). 7.1.121N2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-6-yl)-pyrimidineamine Inlike manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-4-N-methyl-1,4-benzoxazinewere reacted to yieldN2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-6-yl)-pyrimidineamine 1HDMSO 8.2 (d, 1H),6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m,1H), 4.05 (m, 2H),3.2 (m, 2H) 2.8 (s, 3H) purity 95 % MS (m/e): 295 (MH⁺). 7.1.122N2-Chloro-5-fluoro-N4-( N-methyl-1,4-benzoxazin-7-yl)-pyrimidineamine Inlike manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-4-N-methyl -1,4-benzoxazinewere reacted to yield N2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-7-yl)-pyrimidineamine 1H DMSO 8.2 (d, 1H),6.8(m, 1H), 6.75 (m, 1H), 6.60 (m,1H), 4.05 (m, 2H), 3.2 (m, 2H) 2.8 (s,3H) purity 94 % MS (m/e): 295 (MH⁺). 7.1.123 N2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-pyrimidineamine In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-4-N-methyl-1,4-benzoxazine-3-one were reacted to yield N2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-pyrimidineamine 1H DMSO 8.2 (d,1H),6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m,1H), 4.73 (s, 2H) 2.8 (s, 3H)purity 96 % MS (m/e): 309 (MH⁺). 7.1.124N2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)-pyrimidineamineIn like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and7-amino-4-N-methyl-1,4-benzoxazine-3-one were reacted toN2-Chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)-pyrimidineamine1H DMSO 8.2 (d, 1H),6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m,1H), 4.68 (s, 2H)2.8 (s, 3H) purity 93 % MS (m/e): 309 (MH⁺). 7.1.125N2-chloro-N4-(3-ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoropyrimidinediamine(R909258) : In like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and ethyl6-amino-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine were reacted toyieldN2-chloro-N4-(3-ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoropyrimidinediamine1H (DMSO-d₆) 8.42 (s, 1H), 8.30 (m, 1H), , 8.05 (m, 1H), 7.43 (m, 1H),5.53 (s, 2H), 4.25 (q, 2H J=6.5 Hz), 1.28 (t, 2H, J=6.5 Hz), purity 90 %MS (m/e): 390 (MH⁺). 7.1.126N2-Chloro-N4-(3,3-dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-pyrimidineamineIn like manner to2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-Amino-3,3-dimethyl-1,4-benzoxazinewere reacted to yieldN2-Chloro-N4-(3,3-dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-pyrimidineamine1H DMSO 8.18 (d, 1H), 6.8 (d, 1H), 6.67 (m, 2H), 3.76 (s, 2H), 1.05 (s,6H) purity 99 % MS (m/e): 309 (MH⁺) 7.1.1272-Chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyrimidineamine(R935241) In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with5-amino-1-(methoxycarbonyl)methyl-indazoline to produce2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ10.04 (s, 1H), 8.28 (d, 1H, J =3.5 Hz), 8.12 (s, 1H),8.00 (dd, 1H, J =1.2 and 4.1 Hz), 7.64 (d, 1H, J =8.8 Hz), 7.58-7.54 (m,1H), 5.39 (s, 2H), 3.66 (s, 3H). 7.1.1282-Chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineamine(R935257) In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine to produce2-chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): ¹H NMR (DMSO-d₆): δ10.08 (s, 1H), 8.31 (s, 1H), 7.91(d, 1H, J =2.3 Hz), 7.74 (d, 1H, J =1.2 Hz), 7.37 (dd, 1H, J =2.3 and8.8 Hz), 7.16 (d, 1H, J =8.8 Hz), 7.14 (d, 1H, J =1.2 Hz), 5.29 (s, 2H).LCMS: ret. time: 18.74 min.; purity: 99%; MS (m/e): 318 (MH⁺). 7.1.1292-Chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine (R935260) Inlike manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with 6-aminoindazole toproduce 2-chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine . ¹H NMR(CDCl₃): δ13.03 (s, 1H), 10.07 (s, 1H), 8.32 (d, 1H, J =3.5 Hz), 8.07(s, 1H), 7.99 (s, 1H), 7.71 (d, 1H, J =8.8 Hz), 7.34 (dd, 1H, J =1.7 and8.8 Hz). LCMS: ret. time: 18.52 min.; purity: 99%; MS (m/e): 263 (MH⁺).7.1.130 2-Chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine(R935265) In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with 5-aminoindazoline. ¹HNMR (CDCl₃): δ9.99 (s, 1H), 8.26 (d, 1H, J =3.5 Hz), 8.07 (s, 1H), 7.99(d, 1H, J =1.1 Hz), 7.53 (dd, 2H, J =1.7 and 8.8 Hz). LCMS: ret. time:18.03 min.; purity: 97%; MS (m/e): 264 (MH⁺). 7.1.1312-Chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine (R935275) In likemanner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine was reacted with 1-aminopyrrole toproduce 2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine. ¹H NMR(CDCl₃): δ11.39 (s, 1H), 8.35 (d, 1H, J =3.5 Hz), 6.83 (t, 2H, J =2.3Hz), 6.07 (t, 2H, J =2.3 Hz). LCMS: ret. time: 18.95 min.; purity: 97%;MS (m/e): 213 (MH⁺). 7.1.1322-Chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine(R926853) A reaction mixture containing2,4-dichloro-5-fluoro-pyrimindine (1.2 equivalents) and3-(tetrazol-5-yl)aniline (1 equivalents) in methanol:water (1:1; v/v)was heated at 60° C. for 24 h. Upon dilution with water andacidification, the solid formed was fitered, washed with water, driedand analyzed to give2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine(R926853). Alternatively this reaction can be achieved by treating2,4-dichloro-5-fluoropyrimidine (1 equivalent) with3-(tetrazol-5-yl)aniline (3 equivalents) in methanol:water (1:1; v/v) at60° C. for 2-3 hours or at room temperature for 24 h to give2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. ¹HNMR (DMSO-d₆): δ10.25 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H, J=3.6 Hz),7.90 (dd, 1H, J=0.9 and 9 Hz), 7.75 (d, 1H, J=7.5 Hz), 7.61 (t, 1H,J=7.8 Hz); LCMS: purity: 90%; MS (m/e): 292 (MH⁺). 7.1.1332-Chloro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-2,4-pyrimidineamine(R950297) A solution of 3,4-dihydro-4-hydroxy-6-amino-2H-1-benzopyranand 2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at70° C. The mixture was diluted with water and the resulting precipitatewas filtered to give2-chloro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-2,4-pyrimidineamineas a pale brown solid. LCMS: purity: 99.3%; MS (m/e): 296.1 (MH⁺).7.1.1342-Chloro-N4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidineamine(R950375) A solution of 3-(p-aminophenyl)-propionic acid and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidineamineas a pale brown solid. LCMS: purity: 93.3%; MS (m/e): 311.98 (M⁻).7.1.1352-Chloro-N4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine(R950298) A solution of 3-carboxy-4-hydroxyaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine asa pale brown solid. LCMS: purity: 87.4%; MS (m/e): 284.1 (MH⁺). 7.1.1362-Chloro-N4-(4-trifluoromethyl-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidineamine(R950390) A solution of 4-trifluoromethyl-3-methoxycarbonylaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(4-trifluoromethyl-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidineamineas a pale brown solid. LCMS: purity: 96.4%; MS (m/e): 366.34 (MH⁺).7.1.1372-Chloro-N4-(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidineamine(R950369) A solution of 3-methylcarbonylaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidineamine as apale brown solid. LCMS: purity: 99.1%; MS (m/e): 266.12 (MH⁺). 7.1.1382-Chloro-N4-(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidineamine(R950370) A solution of 3-phenylcarbonylaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidineamine as apale brown solid. LCMS: purity: 78.5%; MS (m/e): 328.16 (MH⁺). 7.1.1392-Chloro-N4-(3-nitrophenyl)-5-fluoro-2,4-pyrimidineamine A solution of3-nitroaniline and 2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirredfor 2 hours at 70° C. The mixture was diluted with water and theresulting precipitate was filtered to give2-chloro-N4-(3-nitrophenyl)-5-fluoro-2,4-pyrimidineamine as a pale brownsolid. ¹H NMR (DMSO): δ10.34 (s, 1H), 8.73 (d, 1H, J =2.4 Hz), 7.66-8.29(m, 4H). 7.1.1402-Chloro-N4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-aminopyridine(R950384) A solution of 3-hydroxymethylen-4-methoxyaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-aminopyridineas a pale brown solid. LCMS: purity: 91.8%; MS (m/e): 266.03 (MH⁻).7.1.141 2-Chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-aminopyridine(R950387) A solution of 3-amino-4-ethoxyaniline and2,4-dichloro-5-fluoro-pyrimidine in MeOH was stirred for 2 hours at 70°C. The mixture was diluted with water and the resulting precipitate wasfiltered to give2-chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-aminopyridine as a palebrown solid. LCMS: purity: 93.2%; MS (m/e): 252.06 (MH⁻). 7.2 Synthesisof Amines and Amine Precursors 7.2.15-Amino-2-(2-hydroxyethyleneoxy)pyridine A methanolic solution (50 mL)of 2-(2-hydroxyethyleneoxy)-5-nitropyridine (0.5 g) was hydrogenated inthe presence of Pd/C (10%; 0.05 g) using a balloon filled with hydrogenfor 2 h. After the filtration through a pad of celite and washing withmethanol the solution was concentrated to give the5-amino-2-(2-hydroxyethyloxy)pyridine. ¹H NMR (CDCl₃): δ7.58 (d, 1H, J=3Hz), 7.05 (dd, 1H, J=2.7 and 8.1 Hz), 6.64 (d, 1H, J=8.7 Hz), 4.36 (m,2H), 3.89 (m, 2H). 7.2.2 4-Chloro-3-methoxyaniline In like manner to thepreparation of 5-amino-2-(2-hydroxyethyleneoxy)pyridine, thehydrogenation of 4-chloro-3-methoxynitrobenzene gave4-chloro-3-methoxyaniline. LCMS: purity: 98%; MS: 199 (M+ acetonitrile).7.2.3 2-[5-Amino-2-oxo-1,3-benzoxazol-3(2H)-yl]acetamide In like mannerto the preparation of 5-amino-2-(2-hydroxyethyleneoxy)pyridine, thehydrogenation of 2-[1,3-benzoxazol-2-oxo-5-nitro-3(2H)-yl)acetamide gave2-[5-amino-2-oxo-1,3-benzoxazol-3(2H)-yl]acetamide. LCMS: purity: 96%;MS: 208 (MH⁺). 7.2.4 7-nitro-1,2,3,4-tetrahydroisoquinoline7-nitro-1,2,3,4-tetrahydroisoquinoline was prepared by nitration of1,2,3,4-tetrahydroisoquinoline according to the following reference:Grunewald, Gary L.; Dahanukar, Vilas H.; Caldwell, Timothy M.;Criscione, Kevin R.; Journal of Medicinal Chemistry (1997), 40(25),3997-4005. 7.2.52-(t-Butoxycarbonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline A mixture of7-nitro-1,2,3,4-tetrahydroisoquinoline (0.55 g, 3.1 mmole),di-t-butyldicarbonate (0.70 g, 3.2 mmole), triethylamine (1.0 mL, 7.7mmole) in dichloromethane (8 mL) was stirred at rt for 8 h. The reactionmixture was diluted with water (50 mL) and stirred for 1 h. The organicphase was separated and washed with brine. Concentration of the organicphase gave 2-(t-butoxycarbonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline.¹H NMR (CDCl₃): δ8.03-7.95 (m, 2H), 7.28 (d, 1H, J=8.4 Hz), 4.66 (s,2H), 3.68 (t, 2H, J=6.0 Hz), 2.92 (t, 2H, J=6.0 Hz),1.49 (s, 9H). 7.2.62,3-Dihydro-6-nitro-4-benzypyranon 3-(p-Nitrophenyl)-propionic acid isdissolved in concentrated sulfuric acid and treated with P₂O₅. Themixture is stirred for 1 hr at room temperature and poured onto ice.Filtration gave 2,3-dihydro-6-nitro-4-benzypyranon as a white solid. ¹HNMR (DMSO): δ8.47 (d, J =3.0 Hz, 1H), 8.35 (dd, J =3.0, 9.0 Hz, 1H),7.29 (d, J =9.0 Hz, 1H), 4.70 (t, J =7.2 Hz, 1H), 2.90 (t, J =7.2 Hz,1H). 7.2.7 3,4-Dihydro-4-hydroxy-6-amino-2H-1-benzopyran A mixture2,3-dihydro-6-nitro-4-benzypyranon and Pd/C (10%) in MeOH washydrogenated at 22° C. for 3 hours (40 psi). The mixture was filteredand concentrated to dryness to give3,4-dihydro-4-hydroxy-6-amino-2H-1-benzopyran as a brown oil. ¹H NMR(DMSO): δ6.40-6.56 (m, 3H), 5.05 (bs, 1H), 4.45 (bs, 1H), 3.94-4.09 (m,2H), 1.76-1.98 (m, 2H). 7.2.8N4-(3,4-Ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R950287) A solution of2-Chloro-5-ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-2,4-pyrimidineaminein EtOH was treated with a 25% aqueous solution of NH₃. The mixture wasstirred for 30 min at 100° C. and purified by flash chromatography onsilica gel to giveN4-(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine as awhite solid. LCMS: purity: 92.3%; MS (m/e): 317.28 (MH⁺, 100). 7.2.93-(N-morpholinocarbonyl)aniline To a 0° C. solution of3-nitrobenzoylchloride (0.50 g, 2.7 mmole) and pyridine (0.27 mL, 3.2mmole) in anhydrous dichloromethane (15 mL) was added morpholine (0.28mL, 3.2 mmole). The reaction mixture was allowed to warm to rt and wasstirred for 20 h. The solvents were removed under vacuum and the residuesuspended in ethyl acetate and washed with 1N HCl. The organic layer waswashed with a saturated solution of NaHCO₃ and brine. Removal of thesolvents under vacuum provided 1-(N-morpholinocarbonyl)-3-nitrobenzenewhich was used without further purification. A mixture of1-(N-morpholinocarbonyl)-3-nitrobenzene (0.64 g) and 10% Pd on activatedcarbon (60 mg) in degassed methanol (65 mL) was stirred under a balloonof H₂ for 2 h. The reaction mixture was filtered through Celite® filteraid and then concentrated under reduced pressure to provide3-(N-morpholinocarbonyl)aniline in quantitative yield. ¹H NMR (CDCl₃):δ7.19-7.14 (m, 1H), 6.75-6.69 (m, 3H), 3.58-3.71 (m, 10H). 7.2.103-(N-propylcarbonyl)aniline In like manner to the preparation of3-(N-morpholinocarbonyl)aniline, 3-nitrobenzoylchloride andn-propylamine were reacted to prepare1-[(N-propylamino)carbonyl]-3-nitrobenzene which underwent hydrogenationto provide 3-(N-propylcarbonyl)aniline. ¹H NMR (CDCl₃): δ7.18 (t, 1H,J=7.5 Hz), 7.13 (t, 1H, J=1.8 Hz), 7.05-7.01 (m, 1H), 6.78 (ddd, 1H,J=1.2, 2.4, and 7.5 Hz), 6.10 (bs, 1H), 3.58-3.53 (bs, 2H), 3.43-3.34(m, 2H), 1.68-1.57 (m, 2H), 0.97 (t, 3H, J=7.2 Hz). 7.2.113-[4-(Ethoxycarbonyl)piperidinocarbonyl]aniline In like manner to thepreparation of 3-(N-morpholinocarbonyl)aniline, 3-nitrobenzoylchlorideand ethyl isonipecotate were reacted to prepare1-[4-(ethoxycarbonyl)piperidinocarbonyl]-3-nitrobenzene which underwenthydrogenation to provide3-[4-(ethoxycarbonyl)piperidinocarbonyl]aniline. 7.2.123-(N-methylcarbonyl)aniline In like manner to the preparation of3-(N-morpholinocarbonyl)aniline, 3-nitrobenzoylchloride and methylaminehydrochloride were reacted to prepare1-[(N-methylamino)carbonyl]-3-nitrobenzene which underwent hydrogenationto provide 3-(N-methylcarbonyl)aniline. ¹H NMR (CDCl₃): δ7.18 (t, 1H,J=7.5 Hz), 7.13 (t, 1H, J=1.8 Hz), 7.04-6.99 (m, 1H), 6.81-6.75 (m, 1H),6.05 (bs, 1H), 3.84 (bs, 2H), 2.99 (d, 3H, J=4.8 Hz). 7.2.137-Amino-1-tetralone In like manner to the preparation of ethyl4-aminophenoxyacetate, hydrogenation of 7-nitro-1-tetralone was carriedout to prepare 7-amino-1-tetralone. ¹H NMR (CDCl₃): δ7.32 (d, 1H, J=2.4Hz), 7.05 (d, 1H, J=8.1 Hz), 6.82 (dd, 1H, J=2.4 and 8.1 Hz), 2.85 (t,2H, J=6.6 Hz), 2.61 (t, 2H, J=6.6 Hz), 2.14-2.04 (m, 2H). 7.2.147-Amino-2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline In likemanner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenationof 2-(t-butoxycarbonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline wascarried out to prepare7-amino-2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline. ¹H NMR(CDCl₃): δ6.92 (d, 1H, J=8.4 Hz), 6.52 (dd, 1H, J=2.4 and 8.4 Hz), 6.44(bs, 1H), 4.47 (s, 2H), 3.63-3.48 (m, 2H), 2.71 (t, 2H, J=5.1 Hz), 1.45(s, 9H). 7.2.15 7-Amino-1,2,3,4-tetrahydroisoquinoline In like manner tothe preparation of ethyl 4-aminophenoxyacetate, hydrogenation of7-nitro-1,2,3,4-tetrahydroisoquinoline was carried out to prepare7-amino-1,2,3,4-tetrahydroisoquinoline. ¹H NMR (DMSO-d ₆): δ9.35 (bs,1H), 6.82 (d, 1H, J=8.1 Hz), 6.45 (dd, 1H, J=2.4 and 8.4 Hz), 6.30 (d,1H, J=2.4 Hz), 5.05 (s, 2H), 4.05 (s, 2H), 3.24 (t, 2H, J=6.6 Hz), 2.78(t, 2H, J=6.6 Hz). 7.2.16 2-(3-aminophenoxy)-N,2-dimethylpropanamide Inlike manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of N,2-dimethyl-2-(3-nitrophenoxy)propanamide was carriedout to prepare 2-(3-aminophenoxy)-N,2-dimethylpropanamide. ¹H NMR(CDCl₃): δ7.03 (t, 1H, J=7.8 Hz), 6.71 (bs, 1H), 6.39 (dd, 1H, J=1.2 and6.9 Hz), 6.29 (dd, 1H, J=2.4 and 9.6 Hz), 6.25-6.22 (m, 1H), 2.86 (d,3H, J=4.2 Hz), 2.86 (d, 3H, J=4.2 Hz), 1.50 (s, 6H). 7.2.17 Ethyl2-(3-aminophenoxy)-2-methylpropanate In like manner to the preparationof ethyl 4-aminophenoxyacetate, hydrogenation of ethyl2-methyl-2-(3-nitrophenoxy)propanate was carried out to prepare ethyl2-(3-aminophenoxy)-2-methylpropanate. ¹H NMR (CDCl₃): δ6.99 (t, 2H,J=8.7 Hz), 6.32 (dt, 1H, J=1.2 and 7.2 Hz), 6.24-6.18 (m, 2H), 4.23 (q,2H, J=7.2 Hz), 1.58 (s, 6H), 1.24 (t, 3H, J=6.9 Hz). 7.2.18N-methyl-2-(5-amino-2-methylphenoxy)acetamide In like manner to thepreparation of ethyl 4-aminophenoxyacetate, hydrogenation ofN-methyl-2-(2-methyl-5-nitrophenoxy)acetamide was carried out to prepareN-methyl-2-(5-amino-2-methylphenoxy)acetamide. ¹H NMR (CD₃OD): δ6.86 (d,1H, J=7.5 Hz), 6.32-6.25 (m, 2H), 4.43 (s, 2H), 2.82 (s, 3H), 2.14 (s,3H). 7.2.19 6-Amino-2-(methoxycarbonyl)-(1H)-indole6-Amino-2-(methoxycarbonyl)-(1H)-indole was prepared according to thefollowing references: 1. Adams, Richard E.; Press, Jeffery B.; Deegan,Edward G.; Synthetic Communications (1991), 12 (5), 675-681. 2. Boger,Dale L.; Yun, Weiya; Han, Nianhe; Johnson, Douglas S.; Biiorganic &Medicinal Chemistry (1995), 3(6), 611-621 7.2.20 Preparation of3-hydroxy-5-(methoxycarbonylmethyleneoxy)aniline and3,5-bis(methoxycarbonylmethyleneoxy)aniline BenzylN-(3,5-dihydroxyphenyl)carbamate To a mixture of 5-aminobenzene-1,3-diol(0.60 g, 3.7 mmole) and sodium hydrogencarbonate (1.4 g, 16 mmole) inTHF/water (15 mL, 1:1 v/v) was added dropwise benzyl chloroformate 1.6mL, 11 mmole). After 3 h at rt, THF was removed under vacuum and theremaining aqueous layer was extracted with ethyl acetate. Purificationby column chromatograpy over silica gel provided benzylN-(3,5-dihydroxyphenyl)carbamate. ¹H NMR (CD₃OD): δ7.42-7.25 (m, 5H),6.46 (d, 2H, J=2.4 Hz), 5.97-5.94 (m, 1H), 5.14 (s, 2H). BenzylN-[3-hydroxy-5-(methoxycarbonylmethyleneoxy) phenyl]carbamate and BenzylN-[3,5-bis(methoxycarbonyl methyleneoxy)phenyl]carbamate In like mannerto the preparation of ethyl 4-nitrophenoxyacetate, benzylN-(3,5-dihydroxyphenyl)carbamate and methyl bromoacetate were reacted togive a mixture of benzylN-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]carbamate ¹H NMR(DMSO-d ₆): δ9.62 (s, 1H), 9.44 (s, 1H), 7.42-7.31 (m, 5H), 6.63 (s,1H), 6.50 (t, 1H, J=2.4 Hz), 5.93 (t, 1H, J=2.4 Hz), 5.10 (s, 2H), 4.63(s, 2H), 3.67 (s, 3H), and benzylN-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]carbamate ¹H NMR (CDCl₃):δ7.38-7.32 (m, 5H), 6.86 (s, 1H), 6.67 (d, 2H, J=1.8 Hz), 6.19 (t, 1H,J=2.4 Hz), 5.16 (s, 2H), 4.57 (s, 4H), 3.78 (s, 6H) which were separatedby column chromatograpy over silica gel.3-Hydroxy-5-(methoxycarbonylmethyleneoxy)aniline In like manner to thepreparation of ethyl 4-aminophenoxyacetate, hydrogenation of benzylN-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]carbamate was carriedout to prepare 3-hydroxy-5-(methoxycarbonylmethyleneoxy)aniline. ¹H NMR(CD₃OD): δ5.87-5.80 (m, 2H), 5.78-5.72 (m, 1H), 4.56 (s, 2H), 3.76 (s,3H). 3,5-Bis(methoxycarbonylmethyleneoxy)aniline In like manner to thepreparation of ethyl 4-aminophenoxyacetate, hydrogenation of benzylN-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]carbamate was carried outto prepare 3,5-bis(methoxycarbonylmethyleneoxy)aniline. ¹H NMR (CD₃OD):δ5.92 (d, 2H, J=2.4 Hz), 5.83 (t, 1H, J=2.4 Hz), 4.58 (s, 4H), 3.78 (s,6H). 7.2.21N4-(3,4-Ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R950287) A solution of2-Chloro-5-ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-2,4-pyrimidineaminein EtOH was treated with a 25% aqueous solution of NH₃. The mixture wasstirred for 30 min at 100° C. and purified by flash chromatography onsilica gel to giveN4-(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine as awhite solid. LCMS: purity: 92.3%; MS (m/e): 317.28 (MH⁺, 100). 7.2.22Ethyl 6-Nitro-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine Was preparedaccording to J. of Heterocyclic Chemistry, 26, 205, (1989) 7.2.23 Ethyl6-Amino-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine Ethyl6-Nitro-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine was reduced shakenin MeOH under 40 p.s.i. H₂ with 20 weight percent of 10% Pd/C (Degussa)for 1 h then filtered and the solvent evaporated. The compound waspurified directly by column chromatograph (EtOAc/hexane) to yield Ethyl6-Amino-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine 1H (DMSO-d₆) 8.41(s, 1H), 6.98 (m, 1H), 6.82 (m, 1H), 6.43 (m, 1H), 5.28 ((s. 2H), 4.23(q, 2H, J=6.2 Hz), 1.27 (t, 2H, J=6.2 Hz) purity 92 % MS (m/e): 232(MH⁺). 7.2.24 6-Amino-3,3-dimethyl-1,4-benzoxazine A mixture of 15 g2-Amino-4-nitrophenol and 40 g Boc₂O in 300 mL CHCl₃ was refluxedovernight filtered and the filtrate was evaporated to near dryness. Theresidue was triturated with hexanes, collected by suction filtration,and dried to yield 2-N-Boc-amino-4-nitrophenol. The2-N-Boc-amino-4-nitrophenol was refluxed in acetone with 15.6 mL of1-Chloro-2-methylpropene and 25 g potassium carbonate overnight. Thereaction mixture was poured into ice-slush, the solid was collected bysuction filtration and washed with water. The solid was dissolved inEtOAc and the organic was washed with 10% NaOH solution, water, thenbrine and dried over MgSO₄. The organic was filtered to remove thedrying agent and evaporated to yield 18 g1-(2-N-Boc-amino-4-nitrophenoxy)-2-methyl-2-propene. 7.8 g of1-(2-N-Boc-amino-4-nitrophenoxy)-2-methyl-2-propene was stirredovernight in methanolic HCl in a round-bottom flask with a septum wiredon, and then heated with a reflux condenser attached at 80° C. for 10minutes. The reaction was cooled and the methanol was removed byrotary-evaporation. The residue was dissolved in 30 mL of 4N HCl,transferred to a new vessel to leave behind any undisolved solids andcooled to 0° C. 1.83 g of NaNO₂ in 5 mL water was added drop wise andthe solution was neutralized with solid sodium bicarbonate. A solutionof 1.64 g NaN₃ in 17 mL water was added slowly drop wise and thereaction was stirred 30 minutes. The precipitate was collected bysuction filtration, washed well with water and dried on the funnel toyield 5.7 g 1-(2-Azido-4-nitrophenoxy)-2-methyl-2-propene. 7 g of1-(2-Azido-4-nitrophenoxy)-2-methyl-2-propene was refluxed in 300 mLbenzene overnight, cooled then evaporated. The crude product wasrecrystalized from EtOAc/Hexanes to yield3-Methyl-6-nitro-azirino[2,1-c]-1,4-benzoxazine in two crops with acombined mass of 5.1 1 g of3-Methyl-6-nitro-azirino[2,1-c]-1,4-benzoxazine was dissolved in 500 mLof MeOH/5% THF, 200 mg of 10% Pd/C (Degussa) was added and the resultingmixture was shaken under 30 p.s.i. H₂ atmosphere for 8 hours. Thereaction mixture was filtered through a pad of celite and the solventevaporated. The residue was dissolved in a minimum amount ofDCM/THF/MeOH and loaded onto a 5 cm by 20 cm 3% MeOH/DCM SiO₂ column andthe compound was eluted isocratically with a small amount of positivepressure. The appropriate fractions were combined and evaporated toyield 590 mg of 6-Amino-3,3-dimethyl-1,4-benzoxazine. 1H (DMSO-d₆) 6.30(d, 1H), 5.75 (d, 1H), 5.65 (dd, 1H), 3.58 (s, 2H), 1.08 (s, 6H) purity99 % MS (m/e): 179 (MH⁺). 7.2.25 Ethyl 4-Aminophenoxyacetate Ethyl4-Nitrophenoxyacetate A dry reaction flask equipped with a refluxcondenser, N₂ inlet and a magnetic stirring bar was charged with3-nitrophenol (76.45 g, 550 mmol), K₂CO₃ (76.45 g, 550 mmol) and dryacetone (500 mL) under N₂ atmosphere. To this at room temperature wasadded ethyl bromoacetate (55.44 mL, 500 mmol) over a period of 15 min.The reaction mixture was refluxed for 16 h, cooled and poured overice-water (4 Kg). The resulting aqueous solution was extracted withCH₂Cl₂ (3 × 500 mL), dried over anhydrous Na₂SO₄ and solvent was removedto obtain 103g (92%) of the desired ethyl 4-nitrophenoxyacetate. ¹H NMR(CDCl₃): δ8.20 (d, 2H, J=8.2 Hz), 6.95 (d, 2H, J=8.1 Hz), 4.72 (s, 2H),4.25 (q, 2H), 1.23 (t, 3H); LCMS: ret. time: 27.07 min.; purity: 100%;MS: 267 (M+ acetonitrile). Ethyl 4-Aminophenoxyacetate A solution ofethyl 4-nitrophenoxyacetate (15 g) in EtOH (400 mL) was hydrogenated at40 PSI for 40 minutes in the presence of 10% Pd/C (1.5 g, 10% byweight). After the filtration through a celite the solvent was removedunder a reduced pressure to obtain ethyl 4-aminophenoxyacetate. ¹H NMR(CDCl₃): δ6.77 (d, 2H, 8.1 Hz), 6.60 (d, 2H, J=8.0 Hz), 4.50 (s, 2H),4.24 (q, 2H), 1.24 (t, 3H); LCMS: ret. time: 12.00 min.; purity: 100%;MS (m/e): 196 (MH⁺). 7.2.26 tert-Butyl 4-Aminophenoxyacetate tert-Butyl4-Nitrophenoxyacetate In like manner to the preparation of ethyl4-nitrophenoxyacetate, 4-nitrophenol and tert-butyl bromoacetate werereacted to prepare tert-butyl 4-nitrophenoxyacetate. ¹H NMR (CDCl₃):δ8.2 (d, 2H, J=8.1 Hz), 6.95 (d, 2H, J=8.2 Hz), 4.60 (s, 2H), 1.42 (s,9H). tert-Butyl 4-Aminophenoxyacetate In like manner to the preparationof ethyl 4-aminophenoxyacetate, hydrogenation of tert-butyl4-nitrophenoxyacetate was carried out to prepare tert-butyl4-aminophenoxyacetate. ¹H NMR (CDCl₃): δ6.74 (d, 2H, J=9 Hz), 6.62 (d,2H, J=9 Hz), 4.42 (s, 2H), 1.42 (s, 9H); LCMS: ret. time: 16.35 min.;purity: 94%; MS (m/e): 224 (MH⁺). 7.2.27 Ethyl 3-AminophenoxyacetateEthyl 3-Nitrophenoxyacetate In like manner to the preparation of ethyl4-nitrophenoxyacetate, 3-nitrophenol and ethyl bromoacetate were reactedto prepare ethyl 3-nitrophenoxyacetate. ¹H NMR (CDCl₃): δ7.88 (dt, 1H,J=1.2 and 8.7 Hz), 7.71 (t, 1H, J=2.4 Hz), 7.45 (t, 1H, J=8.4 Hz), 7.27(dt, 1H, J=2.4 and 8.4 Hz), 4.70 (s, 2H), 4.29 (q, 2H, J=6.9 Hz), 1.30(t, 3H, J=6.9 Hz); LCMS: ret. time: 27.28 min.; purity: 96%. Ethyl3-Aminophenoxyacetate In like manner to the preparation of ethyl4-aminophenoxyacetate, hydrogenation of ethyl 3-nitrophenoxyacetate wascarried out to prepare ethyl 3-aminophenoxyacetate. ¹H NMR (CDCl₃):δ7.05 (t, 1H, J=7.2 Hz), 6.30 (m, 3H), 4.56 (s, 2H), 4.25 (q, 2H, J=7.2Hz), 1.29 (t, 3H, J=6.9 Hz); LCMS: ret. time: 10.69 min.; purity: 96%;MS (m/e): 196 (MH⁺). 7.2.28 (±)-Ethyl 2-(4-Aminophenoxy)propionate Inlike manner to the preparation of ethyl 4-aminophenoxyacetate,hydrogenation of ethyl (±)-2-(4-nitrophenoxy)propionate was carried outto prepare (±) ethyl 2-(4-aminophenoxy)propionate. ¹H NMR (CDCl₃): δ6.70(d, 2H), 6.58 (d, 2H), 4.60 (m, 1H), 4.20 (q, 2H), 3.2 (bs, 2H), 1.45(d, 3H), 1.22 (t, 3H). 7.2.29 N-Methyl 3-Aminophenoxyacetamide N-Methyl3-Nitrophenoxyacetamide A mixture of ethyl 3-nitrophenoxyacetate (9.12g, 40 mmol), methylamine hydrochloride (26.8 g, 400 mmol) anddiisopropylethylamine (35.5 mL, 200 mL) in MeOH (100 mL) was stirred ina pressure vial at 90° C. for 6 h. The reaction was cooled to roomtemperature, diluted with water (1 liter), the solid formed wasfiltered, washed with water and dried to get the desired N-methyl3-nitrophenoxyacetamide (8 g, 95%). ¹H NMR CDCl₃): δ7.91 (dd, 1H, J=1.8and 8.1 Hz), 7.78 (t, 1H, J=2.4 Hz), 7.50 (t, 1H, J=8.7 Hz), 7.29 (dd,1H, J=1.8 and 8.4 Hz), 6.50 (bs, 2H), 4.57 (s, 2H), 2.95 and 2.93 (2s,3H); LCMS: ret. time: 17.54 min.; purity: 100%; MS (m/e): 211 (MH⁺).N-Methyl 3-Aminophenoxyacetamide In like manner to the preparation ofethyl 4-aminophenoxyacetate, the hydrogenation of N-methyl3-nitrophenoxyacetamide (8 g, 39 mmol) was conducted to give the desiredN-methyl 3-aminophenoxyacetamide (6 g, 86%). ¹H NMR (CD₃OD): δ6.99 (t,1H, J=8.1 Hz), 6.37-6.25 (m, 3H), 4.41 (s, 2H), 2.80 (s, 3H); LCMS: ret.time: 19.80 min.; purity: 100%. 7.2.30.2-Methoxycarbonyl-5-aminobenzofuran (R926610)2-Methoxycarbonyl-5-nitrobenzofuran (R926609) To a suspension of5-nitro-2-benzofurancarboxylic acid (5 g, 24.15 mmol) in CH₂Cl₂ (250 mL)at 0° C. was added DMF (0.100 mL) followed by (COCl)₂ (2M in CH₂Cl₂,36.23 mL, 72.46 mL) over a period of 10 min. The reaction was stirred at0° C. for 1 h and then at room temperature for 30 min. The reactionsolvent was removed under a reduced pressure, dried under high vacuumand again suspended in CH₂Cl₂ (250 mL). The solution was cooled to 0°C., were added pyridine (4.8 mL, 48.03 mmol) followed by MeOH (10 mL,excess) and stirred overnight. The extractive work-up with CH₂Cl₂ gavethe expected 2-methoxycarbonyl-5-nitrobenzofuran (R926609). ¹H NMR(CDCl₃): δ8.66 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4 and 9.6 Hz), 7.71(d, 1H, J=9.3 Hz), 7.65 (s, 1H), 4.01 (s, 3H); LCMS: ret. time: 26.94min. 2-Methoxycarbonyl-5-aminobenzofuran (R926610) In like manner to thepreparation of ethyl 4-aminophenoxyacetate, the hydrogenation of2-methoxycarbonyl-5-nitrobenzofuran (2 g) in MeOH gave2-methoxycarbonyl-5-aminobenzofuran. ¹H NMR (CDCl₃): δ7.38 (bt, 2H),6.90 (bd, 1H), 6.85 (bdd, 1H), 3.98 (s, 3H). 7.2.31 Methyl2-(2-methyl-5-nitrophenoxy)acetate In like manner to the preparation ofethyl 4-nitrophenoxyacetate, 2-methyl-5-nitrophenol and methylbromoacetate were reacted to prepare methyl2-(2-methyl-5-nitrophenoxy)acetate. ¹H NMR (CD₃OD): δ7.80 (dd, 1H, J=2.4and 8.1 Hz), 7.65 (d, 1H, J=2.4 Hz), 7.38 (d, 1H, J=8.1 Hz), 4.90 (s,2H), 3.80 (s, 3H), 2.36 (s, 3H). 7.2.32 Ethyl2-methyl-2-(3-nitrophenoxy)propanate A mixture of 3-nitrophenol (0.50 g,3.6 mmole), ethyl bromodimethylacetate (0.64 g, 3.3 mmole), K₂CO₃ (1.3g, 9.4 mmole), potassium iodide (catalytic) in absolute ethanol (8 mL)was heated at 70° C. for 18 h. The reaction mixture was cooled, pouredinto a saturated solution of NaHCO3, and extracted with dichloromethane.The product, ethyl 2-methyl-2-(3-nitrophenoxy)propanate, was obtainedafter purification by column chromatography over silica gel. ¹H NMR(CDCl₃): δ7.85 (dt, 1H, J=1.2 and 8.1 Hz), 7.68 (t, 1H, J=2.4 Hz), 7.40(t, 1H, J=8.4 Hz), 7.19-7.13 (m, 1H), 4.26 (q, 2H, J=7.2 Hz), 1.64 (s,6H), 1.26 (t, 3H, J=7.21), 7.2.33N-Methyl-2-(2-methyl-5-nitrophenoxy)acetamide In like manner to thepreparation of N-methyl 3-nitrophenoxyacetamide, methyl2-methyl-5-nitrophenoxyacetate and methylamine hydrochloride werereacted to prepare N-methyl-2-(2-methyl-5-nitrophenoxy)acetamide. ¹H NMR(CD₃OD): δ7.82 (dd, 1H, J=2.4 and 8.1 Hz), 7.69 (d, 1H, J=2.4 Hz), 7.40(d, 1H, J=8.1 Hz), 4.66 (s, 2H), 2.83 (s, 3H), 2.40 (s, 3H). 7.2.34N,2-Dimethyl-2-(3-nitrophenoxy)propanamide In like manner to thepreparation of ethyl 2-methyl-2-(3-nitrophenoxy)propanate, 3-nitrophenoland N,2-dimethyl-2-bromopropanamide (prepared according to the followingreference: Guziec, Frank S., Jr.; Torres, Felix F. Journal of OrganicChemistry (1993), 58(6), 1604-6) were reacted to prepareN,2-dimethyl-2-(3-nitrophenoxy)propanamide. ¹H NMR (CDCl₃): δ7.94 (dt,1H, J=1.2 and 8.1 Hz), 7.78 (t, 1H, J=2.4 Hz), 7.45 (t, 1H, J=8.4 Hz),7.22 (ddd, 1H, J=1.2, 2.4, and 8.1 Hz), 6.61 (bs, 1H), 2.89 (d, 3H,J=5.1 Hz), 1.55 (s, 6H). 7.2.354-Amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene4-Nitro-[(1H,1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene A mixture of2-cyanomethoxy-4-nitrophenyl (5.8 g, 32.6 mmol), sodium azide (6.3 g,98.0 mmol) and ammonium chloride (8.5 g, 163.3 mmol) was suspended inDMF (100 mL) containing acetic acid (1 mL) and the mixture heated at 70°C. After 17 h, the reaction was cooled to room temperature and 2 Naqueous hydrochloric acid (100 mL) was added. The solid whichprecipitated out of the reaction mixture was collected by filtration,washed with water (2 × 20 mL) then hexane (30 mL), affording compound4-nitro-[(1H,1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene (6.7 g, 99%) asan orange solid: ¹H NMR (300 MHz, DMSO-d6) δ8.25 (d, J =9.2 Hz, 2H),7.29 (d, J =9.1 Hz, 2H), 5.68 (s, 2H); ESI MS m/z 220 [C₈H₇N₅O₃ - H].4-Amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene A mixture of4-nitro-[(1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene (6.7 g, 30.4 mmol)and 5 wt % palladium on carbon (700 mg) suspended inethanol/concentrated hydrochloric acid (14:1, 150 mL) was hydrogenatedin a sealed vessel at 50 psi. The mixture was shaken until no furtherhydrogen uptake was observed, after which the reaction was filteredthrough diatomaccous earth with chloroform and the filtrate concentratedto afford crude product. Purification by flash chromatography (7:2.5:0.5CHCl₃/CH₃OH/NH₄OH) afforded4-amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy)]benzene as a brown solid:¹H NMR (300 MHz, DMSO-d6) δ6.76 (d, J =8.7 Hz, 2H), 6.52 (d, J =8.7 Hz,2H), 5.07 (s, 2H); ESI MS m/z 190 [C₈H₉N₅O - H]⁻. 7.2.364-Amino-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene4-Nitro-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene and4-Nitro-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene A mixtureof 4-nitro-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene (10.00 g, 45.2mmol), cesium carbonate (22.09 g, 67.8 mmol) and methyl iodide (7.70 g,54.3 mmol) in DMF (200 mL) was stirred at room temperature for 24 h. Thereaction mixture was concentrated to remove most of the DMF and thecrude residue was partitioned between chloroform (100 mL) and water (50mL). The organic phase was separated, washed with brine, dried (Na₂SO₄)and concentrated to afford crude product as a orange solid. Purificationby flash chromatography (chloroform) afforded4-nitro-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene: ¹H NMR(300 MHz, DMSO-d6) δ8.26 (d, J =9.2 Hz, 2H), 7.31 (d, J =9.2 Hz, 2H),5.72 (s, 2H), 4.15 (s, 3H); and4-nitro-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene: ¹H NMR(300 MHz, DMSO-d6) δ8.24 (d, J =9.3 Hz, 2H), 7.29 (d, J =9.3 Hz, 2H),5.58 (s, 2H), 4.41 (s, 3H).4-Amino-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene A mixtureof 4-nitro-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (3.60g, 15.3 mmol) and 5% Pd/C (0.40 g) in 14:1 ethanol/concentratedhydrochloric acid (75 mL) was shaken at room temperature in a atmosphereof hydrogen at 50 psi. After 4 h no further hydrogen uptake wasobserved. The reaction mixture was filtered through diatomaceous earth,the solids washed with a 6:3:1 chloroform/methanol/concentrated ammoniumhydroxide solution and the filtrate concentrated to afford crude4-amino-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene, whichwas purified by flash chromatography (95:5 chloroform/ methanol): ¹H NMR(300 MHz, DMSO-d6) δ7.48 (br s, 2H), 6.79 (d, J =6.9 Hz, 2H), 6.55 (d, J=6.9 Hz, 2H), 5.36 (s, 2H), 4.10 (s, 3H). 7.2.374-Amino-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene A mixtureof 4-nitro-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene (3.60g, 15.3 mmol) and 5% Pd/C (0.40 g) in 14:1 ethanol/concentratedhydrochloric acid (75 mL) was shaken at room temperature in a hydrogenatmosphere at 50 psi. After 3 h no further hydrogen uptake was observed.The reaction mixture was filtered through diatomaceous earth, the solidswashed with a 6:3:1 chloroform/methanol/concentrated ammonium hydroxidesolution and the filtrate concentrated to afford crude4-amino-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene, which waspurified by flash chromatography (95:5 chloroform/ methanol): ¹H NMR(300 MHz, DMSO-d6) δ6.80 (br s, 2H), 6.75 (d, J =9.0 Hz, 2H), 6.50 (d, J=9.0 Hz, 2H), 5.17 (s, 2H), 4.37 (s, 3H). 7.2.382-Ethoxycarbonyl-5-aminoindole (R926611) In like manner to thepreparation of ethyl 4-aminophenoxyacetate, the hydrogenation of2-ethoxycarbonyl-5-nitroindole gave the 2-ethoxycarbonyl-5-aminoindol.LCMS: ret. time: 13.44 min.; purity: 93%; MS (m/e): 205 (MH⁺). 7.2.395-[(4-Aminophenoxy)methyl]-3-phenyl-1,2,4-oaxadiazole Preparation of5-[4-(Nitrophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole 4-Nitrophenol (0.36g, 2.56 mmole), 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (0.5 g, 2.56mmole) and anhydrous K₂CO₃ (0.39 g, 2.82 mmole) were dissolved inanhydrous acetone (20 mL) and heated to reflux for 12 h. Reactionmixture was cooled and the solvent removed under vacuum. The crude solidformed was collected by filtration, washed with water and dried undervacuum to provide 5-[(4-nitrophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole(0.70 g, 92%). ¹H NMR (CDCl₃): δ8.25 (d, 2H, J=8.8 Hz), 8.08 (dd, 2H,J=8.2 Hz), 7.52-7.49 (m, 3H), 7.13 (d, 2H, J=8.8 Hz), 5.45 (s, 2H).Preparation of 5-[(4-Aminophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole The5-[(4-nitrophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole (0.5 g, 1.68 mmole)was dissolved in methanol:methylenechloride (1:1) (120 mL). Aqueoussolution of (15 mL) sodium hydrosulfite (0.88 g, 5.05 mmole) and K₂CO₃(0.70 g, 5.06 mmole ) was added dropwise under nitrogen for 10 min. Thecontents were allowed to stir at room temperature. After consumption ofstarting material, reaction mixture was concentrated, diluted with watertill the homogeneous layer formed. The aqueous layer was extracted withseveral times with ethylacetate and methylene chloride. The turbidorganic layers were combined, dried with anhydrous Na₂SO₄ andconcentrated. Purification of the solid concentrate by silica gelchromatography provided5-[(4-aminophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole (0.23 g, 51%). ¹HNMR (CDCl₃): δ8.11 (m, 2H), 7.52-7.46 (m, 3H), 6.87 (d, 2H, J=8.8 Hz),6.64 (d, 2H, J=8.8 Hz), 5.26 (s, 2H), 3.49 (br s, 2H). Preparation of5-[(4-Nitrophenoxy)methyl]-3-methyl-1,2,4-oxadiazole A mixture of4-nitrophenoxy acetic acid (2.25 g, 11.4 mmole), acetamideoxime,triethylamine hydrochloride (3.85 g, 27.62 mmole), EDCI.HCl (4.37 g,22.79 mmole) and diisopropylethylamine (7.42 g, 57.40 mmole) inanhydrous THF (250 ml) was refluxed for 18 h. The unhomogenous browncolored reaction mixture was quenched with water and extracted withEtOAc (3 × 300 mL). The combined organic layers washed successively withaqueous NaHCO₃, brine and dried over anhydrous Na₂SO₄. Removal ofsolvent and purified by chromatographic purification provided5-[(4-nitrophenoxy)methyl]-3-methyl-1,2,4-oxadiazole (1.62 g, 60 %). ¹HNMR (CDCl₃): δ8.24 (d, 2H, J=8.8 Hz), 7.08 (d, 2H, J=8.8 Hz), 5.36 (s,2H), 2.44 (s, 3H). Preparation of5-[(4-Aminophenoxy)methyl]-3-methyl-1,2,4-oxadiazole In like manner tothe preparation of 5-[(4-aminophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole,5-(4-nitrophenoxymethyl)-3-methyl-1,2,4-oxadiazole was reacted withaqueous solution of sodium hydrosulfite and K₂CO₃ to prepare5-[(4-aminophenox)ymethyl]-3-methyl-1,2,4-oxadiazole. ¹H NMR (CDCl₃):δ6.82 (d, 2H, J=8.8 Hz), 6.63 (d, 2H, J=8.8 Hz), 5.15 (s, 2H), 3.38 (brs, 2H), 2.41 (s, 3H). 7.2.40 Ethyl 2-(4-aminophenyl)-2-methylpropionateEthyl 2-methyl-2-(4-nitrophenyl)propionate A dry reaction flask chargedwith ethyl 4-nitrophenylacetate (5.0 g, 23.89 mmole), iodomethane (8.48g, 3.72 mL, 59.74 mmole), 18-crown-6 (1.57 g, 5.93 mmole) in dry THF(200 mL) was cooled to -78° C. under nitrogen atmosphere. While stirringthe contents, t-BuOK (5.90 g, 52.57 mmole) was added portionwise. Theresulting violet precipitate was stirred at -78° C. for 2 h and allowedthe contents to warm to room temperature. The reaction was stirred atroom temperature for 6 h. At this time, once again the contents werecooled to -78° C. another portion of iodomethane, t-BuOK, and 18-crown-6were added successively and stirred at the same temperature for 2 h. Thereaction was allowed to warm to room temperature and stirred overnight.The reaction was quenched with saturated aq. NH₄Cl (75 mL), theresulting homogenous mixture extracted with ether (4 × 200 mL), driedover anhydrous Na₂SO₄, and concentrated. The concentrate was purified bysilica gel column chromatography with 1%EtOAc/hexanes to provide ethyl2-methyl-2-(4-nitrophenyl)propionate as a pale yellow oil (2.38, 42%).¹H NMR (CDCl₃): δ8.17 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 4.12(qt, 2H, J=7.0 Hz), 1.60 (s, 6H), 1.17 (t, 3H, J=7.0 Hz).Ethyl-2-(4-aminophenyl)-2-methylpropionate In like manner to thepreparation of ethyl 4-aminophenoxyacetate, the hydrogenation of ethyl2-methyl-2-(4-nitrophenyl)propionate providedethyl-2-(4-aminophenyl)-2-methylpropionate. ¹H NMR (CDCl₃): δ7.16 (d,2H, J=8.8 Hz), 6.63 (d, 2H, J=8.8 Hz), 4.09 (qt, 2H, J=7.0 Hz), 3.62 (brs, 2H), 1.52 (s, 6H), 1.17 (t, 3H, J=7.0 Hz). 7.2.41 Anilinessubstituted with 1,3,4-oxadiazole moietiesN′1-(3-Chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide To a solution of3-chlorobenzohydrazide (1 equivalent) and pyridine (2 equivalents) inCH₂Cl₂ at 0° C. was added a CH₂Cl₂ solution of 3-nitrobenzoyl chloride(1 equivalents) and stirred at 0° C. for 1 h and then at roomtemperature for overnight. The resulting solution was concentrated anddiluted with water, basified with NaHCO₃, the solid was filtered, washedwith water, dried and analyzed to obtainN′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide. ¹H NMR (DMSO-d₆):δ10.99 (s, 1H), 10.79 (s, 1H), 8.73 (bs, 1H), 8.43 (bdd, 1H, J=1.2 and8.1 Hz), 8.33 (bdd, 1J, J=8.4 Hz), 7.95 (s, 1H), 7.87 (m, 2H), 7.67(bdd, 1H, J=1.2 and 8.1 Hz), 7.57 (t, 1H, J=7.8 Hz); LCMS: purity: 85%;MS (m/e): 320 (MH⁺).[2-(3-Chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene A suspension ofN′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide (0.321 g) in POCl₃(3 mL) was stirred at 90° C. for 24 h. The resulting clear solution wasquenched with ice-water, solid obtained was filtered washed with water,dried and analyzed to give[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene. ¹H NMR(DMSO-d₆): δ8.86 (t, 1H, J=1.8 Hz), 8.59 (dt, 1H, J=1.8 and 8.4 Hz),8.48 (m, 1H), 8.25 (t, 1H, J=1.8 Hz), 8.16 (dt, 1H, J=1.2 and 7.5 Hz),7.93 (t, 1H, J=8.1 Hz), 7.75 (m, 1H), 7.66 (t, 1H, J=7.5 Hz), LCMS:purity: 86%; MS (m/e): 302 (MH⁺). Reduction of[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene Thehydrogenation of[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene (0.2 g) using10% Pd/C (0.04 g) in MeOH (200 mL) at 15 PSI for 1 h gave a mixture oftwo products viz.3-amino-[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]benzene and3-amino-(2-phenyl-1,3,4-oxadiazol-5-yl)benzene which were separated bysilica gel column chromatography using n-hexanes then n-hexanes: 5-10%EtOAc as a solvent system.3-Amino-[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]benzene: ¹H NMR(DMSO-d₆): δ8.08 (m, 2H), 7.64 (m, 4H), 7.42 (m, 1H), 7.10 (m, 1H);LCMS: purity: 82%; MS (m/e): 272 (MH⁺).3-Amino-(2-phenyl-1,3,4-oxadiazol-5-yl)benzene: ¹H NMR (DMSO-d₆): δ8.13(m, 1H), 7.54 (m, 5H), 7.30 (m, 1H), 6.86 (dd, 1H, J=1.5 and 8.1 Hz);LCMS: purity: 93%; MS (m/e): 238 (MH⁺).N′1-(Ethoxycarbonylmethylenecabonyl)-3-nitrobenzene-1-carbohydrazide Inlike manner to the preparation ofN′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide, the reaction of3-nitrobenzoyl chloride with ethoxycarbonylmethlenecarbohydrazide gaveN′1-(ethoxycarbonylmethylenecabonyl)-3-nitrobenzene-1-carbohydrazide. ¹HNMR (CD₃OD): δ8.74 (m, 1H), 8.44 (dd, 1H, 1.8 and 8.1 Hz), 8.25 (bd, 1H,J=8.4 Hz), 7.76 (t, 1H, J=8.4 Hz), 4.22 (q, 2H, J=6.9 Hz), 3.44 (bs,2H), 1.29 (t, 3H, J=6.8 Hz); LCMS: purity: 93%; MS (m/e): 296 (MH⁺).[2-(Ethoxycarbonylmethylene)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene Inlike manner to the preparation of[2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene the reaction ofPOCl3 withN′1-(ethoxycarbonylmethylenecabonyl)-3-nitrobenzene-1-carbohydrazidegave [2-(ethoxycarbonylmethylene)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene.¹H NMR (CDCl₃): δ8.88 (t, 1H, J=1.8 Hz), 8.42 (m, 2H), 7.74 (t, 1H,J=7.5 Hz), 4.27 (q, 2H, J=7.2 Hz), 4.08 (s, 2H), 1.31 (t, 3H, J=7.2 Hz);LCMS: purity: 95%; MS (m/e): 278 (MH⁺). 7.2.42 Synthesis of(±)-5-Amino-(2,3-dihydro-2-methoxycarbonyl)benzofuran2-Methoxycarbonyl-5-nitrobenzofuran A mixture of2-carboxy-5-nitrobenzofuran (2.0 g), MeOH (10 mL) and Concentrated H₂SO₄(2.1 mL) was heated in a sealed tube at 60° C. for 3 h. Upon cooling tothe room temperature it was quenched with ice-water and carefullybasified with addition of NaHCO₃. The solid obtained was filtered,washed with water, dried and analyzed to give2-methoxycarbonyl-5-nitrobenzofuran. ¹H NMR (CDCl₃): δ8.66 (d, 1H, J=2.4Hz), 8.36 (dd, 1H, J=2.4 and 9.6 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.65 (s,1H), 4.01 (s, 3H); LCMS: purity: 97%; MS (m/e): 222 (MH⁺).(±)-5-Amino-(2,3-dihydro-2-methoxycarbonyl)benzofuran A suspension of2-methoxycarbonyl-5-nitrobenzofuran (2.0 g), 10% Pd/C (2.0 g), Na₂SO₄(2.0 g) in MeOH (500 mL) was hydrogenated at 55 PSI for 3 days. Theresulting solution was filtered through a pad of celite, concentratedand chromatographed using n-hexanes then 10%, 20% EtOAc/n-hexanes togive (±)-5-amino-(2,3-dihydro-2-methoxycarbonyl)benzofuran. ¹H NMR(CDCl₃): δ6.69 (d, 1H, J=8.1 Hz), 6.56 (d, 1H, J=1.2 Hz), 6.48 (dd, 1H,J=1.8 and 7.5 Hz), 5.14 (dd, 1H, J=6.6 and 7.2 Hz), 3.79 (s, 3H), 3.47(dd, 1H, J=10.5 and 10.8 Hz), 3.26 (dd, 1H, J=7.2 and 6.6 Hz); LCMS:purity: 100%; MS (m/e): 194 (MH⁺). 7.2.433-[1-Bis(ethoxycarbonyl)ethoxy]aniline Preparation of Diethyl2-methyl-2-(3-nitrophenoxy)malonate Diethyl 2-bromo-2-methylmalonate(1.0 g, 3.95 mmole) was added to a stirred suspension of potassiumfluoride (0.57 g, 9.8 mmole) in dry DMF (5 mL). After stirring for 20min at room temperature, 3-nitrophenol (0.55 g, 3.95 mmole) was added.The resulting mixture was stirred at 60° C. for 6 h, cooled to roomtemperature, diluted with water (30 mL) and extracted with ethyl acetate(3 × 200 mL). The organic layer was washed with aq.1N NaOH (2 × 75 mL),dried over anhydrous Na₂SO₄, filtered and evaporated in vacuo to providediethyl 2-methyl-2-(3-nitrophenoxy)malonate (0.89 g, 80%). ¹H NMR(CDCl₃): δ7.92 (dd, 1H, J =2.3 and 8.2 Hz), 7.82 (t, 1H, J =2.3 Hz),7.41 (t, 1H, J =8.2 Hz), 7.30 (dd, 1H, J =2.3 and 8.2 Hz), 4.28 (qt, 4H,J =7.0 Hz), 1.81 (s, 3H), 1.26 (t, 6H, J =7.0 Hz). Preparation of3-[1-Bis(ethoxycarbonyl)ethoxy]aniline Diethyl2-methyl-2-(3-nitrophenoxy)malonate (0.75 g, 2.40 mmole) was dissolvedin toluene: ethanol (1:1, 100 mL), transferred to par shaker bottlecontaining Pd/C (0.15 g) and anhydrous Na₂SO₄ (5.0 g) in the presence ofnitrogen atmosphere. The resulting mixture was treated with hydrogen (30PSI) till the disappearance of diethyl2-methyl-2-(3-nitrophenoxy)malonate (2 h). The mixture was filteredthrough celite covered with anhydrous Na₂SO₄ followed by washing thecelite pad with EtOAc. The filtrated was concentrated and dried undervacuo to furnish 3-[1-bis(ethoxycarbonyl)ethoxy]aniline in quantitativeyield . ¹H NMR (CDCl₃): δ6.98 (t, 1H, J =8.2 Hz), 6.37-6.28 (m, 3H),4.26 (qt, 4H, J =7.0 Hz), 3.65 (br s, 2H), 1.72 (s, 3H), 1.24 (t, 6H, J=7.0 Hz). 7.2.44 Preparation of4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan Preparation of4-(4-nitrophenoxymethyl)-2-methoxycarbonyl-furan 3-Nitrophenol (1.0 g,7.19 mmole), methyl 5-(chloromethyl)-2-furoate (1.38 g, 7.90 mmole) andanhydrous K₂CO₃ (1.19 g, 8.60 mmole) in acetone (30 mL) were refluxedfor 8 h. The reaction mixture was cooled and diluted with water. Theresultant white solid was filtered, washed with water and air driedovernight to give 1.81 g (90%) of the desired product. ¹H NMR (CDCl₃):δ7.86 (dd, 1H, J =2.3 and 8.2 Hz), 7.80 (t, 1H, J =2.3 Hz), 7.45 (t, 1H,J =8.2 Hz), 7.27 (dd, 1H, J =2.3 and 8.2 Hz), 7.17 (d, 1H, J =3.5 Hz),6.58 (d, 1H, J =3.5 Hz), 5.13 (s, 2H), 3.90 (s, 3H). Preparation of4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan In like manner to thereduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate,4-(4-nitrophenoxymethyl)-2-methoxycarbonyl-furan was reduced to provide4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan. ¹H NMR (CDCl₃): δ7.15(d, 1H, J =3.5 Hz), 7.05 (t, 1H, J =8.2 Hz), 6.50 (d, 1H, J =3.5 Hz),6.37-6.27 (m, 3H), 5.01 (s, 2H), 3.89 (s, 3H). 7.2.45 Preparation of6-amino-1-(methoxycarbonyl)methylindazoline Preparation of1-(methoxycarbonyl)methyl-6-nitroindazoline To a solution of6-nitroindazoline (2.0 g, 12.25 mmole) in dry DMF was added anhydrousK₂CO₃ (1.84 g, 13.31 mmole) and methyl 2-bromoacetate (2.04 g, 13.33mmole). The resulting mixture was stirred at room temperature for 12 h.The reaction mixture was quenched with water and the resulting solid wascollected by filtration, washed with excessive water, and air dried. Theyellow solid collected was purified by silica gel column chromatographyusing gradient solvent system to furnish two products. The desiredproduct (1.12 g, 41%) with high Rf value on the TLC in 30% EtOAc :hexanes was collected. In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate,1-(Methoxycarbonyl)methyl-6-nitro-indazoline was reduced to provide6-amino-1-(methoxycarbonyl)methylindazoline. ¹H NMR (CDCl₃): δ7.73 (d,1H, J =1.1 Hz), 7.35 (d, 1H, J =8.2 Hz), 6.49 (dd, 1H, J=1.8 and 8.8Hz), 6.39 (s, 1H), 5.34 (br s, 2H), 5.10 (s, 2H), 3.64 (s, 3H).Preparation of 1-(methoxycarbonyl)methyl-5-nitroindazoline In likemanner to the preparation of1-(methoxycarbonyl)methyl-6-nitroindazoline,1-(methoxycarbonyl)methyl-5-nitroindazoline was prepared by alkylationof 5-nitroindazoline with methyl 2-bromoacetate in presence of K₂CO₃.The desired product (1.34 g, 46%) with high Rf value on the TLC in 30%EtOAc : hexanes was collected by silica gel column chromatographicpurification. ¹H NMR (CDCl₃): δ8.75 (d, 1H, J =1.8 Hz), 8.30 (dd, 1H, J=2.3 and 8.2 Hz), 8.26 (s, 1H), 7.40 (d, 1H, J =8.2 Hz), 5.22 (s, 2H),3.78 (s, 3H). Preparation of 5-amino-1-(methoxycarbonyl)methylindazolineIn like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate,1-(Methoxycarbonyl)methyl-5-nitro-indazoline was reduced to provide5-amino-1-(methoxycarbonyl)methylindazoline. ¹H NMR (CDCl₃): δ7.84 (d,1H, J =2.3 Hz), 7.15 (d, 1H, J =8.8 Hz), 6.95 (d, 1H, J=2.3 Hz), 6.88(dd, 1H, J =2.3 and 8.8 Hz), 5.09 (s, 2H), 3.73 (s, 3H). Preparation of1-(2-ethoxycarbonylethyl)-6-nitroindazoline In like manner to thepreparation of 1-(methoxycarbonyl)methyl-6-nitroindazoline,1-(ethoxycarbonyl)ethyl-6-nitroindazoline was prepared by alkylation of6-nitroindazoline with ethyl 3-bromopropionate in presence of K₂CO₃. Thedesired product (58%) with high Rf value on the TLC in 30% EtOAc :Hexanes was collected by silica gel column chromatographic purification.¹H NMR (CDCl₃): δ8.49 (s, 1H), 8.12 (s, 1H), 8.01 (dd, 1H, J =1.7 and8.8 Hz), 7.82 (d, 1H, J =8.8 Hz), 4.74 (t, 2H, J =6.4 Hz), 4.09 (qt, 2H,J =7.0 Hz), 3.03 (t, 2H, J =6.4 Hz), 1.18 (t, 3H, J =7.0 Hz).Preparation of 6-amino-1-(2-ethoxycarbonylethyl)indazoline In likemanner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate,1-(2-ethoxycarbonylethyl)-6-nitroindazoline was reduced to provide6-amino-1-(2-ethoxycarbonylethyl)indazoline. ¹H NMR (CDCl₃): δ7.81 (s,1H), 7.46 (d, 1H, J =8.8 Hz), 6.60 (app s, 1H), 6.55 (dd, 1H, J =2.3 and8.8 Hz), 4.51 (t, 2H, J =7.0 Hz), 4.11 (qt, 2H, J =7.0 Hz), 3.52 (br s,2H), 2.91 (t, 2H, J =7.0 Hz), 1.18 (t, 3H, J =7.0 Hz). Preparation of1-(2-ethoxycarbonylethyl)-5-nitroindazoline In like manner to thepreparation of 1-(methoxycarbonyl)methyl-5-nitroindazoline,1-(ethoxycarbonyl)ethyl-5-nitroindazoline was prepared by alkylation of5-nitroindazoline with ethyl 3-bromopropionate in presence of K₂CO₃. Thedesired product (43%) with high Rf value on the TLC in 30% EtOAc :Hexanes was collected by silica gel column chromatographic purification.¹H NMR (CDCl₃): δ8.70 (d, 1H, J =1.7 Hz), 8.27 (dd, 1H, J =2.3 and 8.8Hz), 8.20 (d, 1H, J =1.7 Hz), 7.59 (d, 1H, J =8.8 Hz), 4.70 (t, 2H, J=6.4 Hz), 4.07 (qt, 2H, J =7.0 Hz), 3.01 (t, 2H, J =6.4 Hz), 1.16 (t,3H, J =7.0 Hz). Preparation of5-amino-1-(2-ethoxycarbonylethyl)indazoline In like manner to thereduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate,1-(2-ethoxycarbonylethyl)-5-nitroindazoline was reduced to provide5-amino-1-(2-ethoxycarbonylethyl)indazoline. ¹H NMR (CDCl₃): δ7.78 (s,1H), 7.30 (d, 1H, J =8.8 Hz), 6.91 (d, 1H, J =2.3 Hz), 6.87 (dd, 1H, J=2.3 and 8.8 Hz), 4.59 (t, 2H, J =6.4 Hz), 4.08 (qt, 2H, J =7.0 Hz),3.02 (br s, 2H), 2.92 (t, 2H, J =7.0 Hz), 1.16 (t, 3H, J =7.0 Hz).Preparation of 5-amino-2-methylindazoline In like manner to thereduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, commerciallyavailable 2-methyl-5-nitroindazoline was reduced to provide5-amino-2-methylindazoline. ¹H NMR (CDCl₃): δ7.61 (s, 1H), 7.53 (d, 1H,J =8.8 Hz), 6.81 (dd, 1H, J =2.3 and 8.8 Hz), 6.75 (d, 1H, J =2.3 Hz),4.13 (s, 3H), 3.85 (br s, 2H). 7.2.46 Preparation of methyl3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate In like manner to thereduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, methyl3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate was reduced to providemethyl 4-[(6-aminoindazol-1-yl)methyl]benzoate. ¹H NMR (CDCl₃): δ7.88(s, 1H), 7.53 (d, 1H, J =8.8 Hz), 7.51 (d, 1H, J =8.8 Hz), 7.50 (d, 1H,J =1.7 Hz), 6.67 (d, 1H, J =8.8 Hz), 6.56 (dd, 1H, J =1.7 and 8.8 Hz),6.45 (d, 1H, J =1.2 Hz), 5.50 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.79(br s, 2H). Preparation of Methyl4-[(6-aminoindazol-2-yl)methyl]benzoate In like manner to the reductionof diethyl 2-methyl-2-(3-nitrophenoxy)malonate, methyl3-methoxy-4-[(6-nitroindazol-2-yl)methyl]benzoate was reduced to providemethyl 4-[(6-aminoindazol-2-yl)methyl]benzoate. ¹H NMR (CDCl₃): δ7.78(s, 1H), 7.56-7.53 (m, 2H), 7.43 (d, 1H, J =8.8 Hz), 6.98 (d, 1H, J =8.2Hz), 6.81 (app s, 1H), 6.58 (dd, 1H, J =1.8 and 8.8 Hz), 5.53 (s, 2H),3.91 (s, 3H), 3.89 (s, 3H). 7.2.47 Preparation of6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazolinePreparation of 6-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline Ester hydrolysis of methyl3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate in presence ofLiOH:H₂O produced the corresponding acid. The acid (1.65 g, 5.04 mmole)thus formed was converted to the acid chloride by reacting with SOCl₂(3.68 mL, 50.45 mmole) at reflux temperature for 5 h. The reactionmixture was cooled to room temperature and concentrated under vacuo. Toacid chloride concentrate dissolved in dry CH₂Cl₂ (75 mL),o-toluylbenzenesulfonamide (0.95 g, 5.54 mmole) and4-(dimethylamino)-pyridine (0.67 g, 5.54 mmole) were added successivelyat room temperature and stirred for 12 h. The reaction mixture wasconcentrated, dissolved in EtOAc (700 mL) and successively treated with2 N HCl (2 × 100 mL), water (150 mL) and brine (100 mL). Usual workupand purification by silica gel column chromatography provided theproduct (1.57 g, 64%). ¹H NMR (DMSO-d₆): δ8.75 (s, 1H), 8.31 (s, 1H),8.00 (d, 1H, J =8.8 Hz), 7.95-7.91 (m, 2H), 7.50 (d, 1H, J =1.2 Hz),7.46-7.27 (m, 4H), 6.92 (d, 1H, J =7.6 Hz), 5.76 (s, 2H), 3.81 (s, 3H),2.54 (s, 3H). Preparation of6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline Inlike manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate,6-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline wasreduced to provide6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline. ¹HNMR (CDCl₃): δ7.96 (dd, 1H, J =1.2 and 8.2 Hz), 7.76 (s, 1H), 7.51 (d,1H, J =1.2 Hz), 7.49-7.44 (m, 1H), 7.37 (d, 2H, J =8.8 Hz), 7.34-7.32(m, 1H), 7.30 (d, 1H, J =8.8 Hz), 6.51-6.47 (m, 2H), 6.35 (s, 1H), 5.35(s, 2H), 3.89 (s, 3H), 2.54 (s, 3H). Preparation of methyl3-methoxy-4-[(5-nitroindazol-1-yl)methyl]benzoate In like manner to thepreparation of methyl 3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate,methyl 3-methoxy-4-[(5-nitroindazol-1-yl)methyl]benzoate was prepared byalkylation of 5-nitroindazoline with methyl(4-bromomethyl)-3-methoxybenzoate in presence of K₂CO₃. The desiredproduct (47%) with high Rf value on the TLC in 30% EtOAc : Hexanes aseluent was collected by silica gel column chromatographic purification.¹H NMR (CDCl₃): δ8.73 (d, 1H, J =1.8 Hz),8.26-8.22 (m, 2H), 7.56 (s,1H), 7.54 (dd, 1H, J =1.8 and 8.2 Hz), 7.49 (d, 1H, J =9.4 Hz), 6.98 (d,1H, J =8.2 Hz), 5.66 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H). Low Rf :Methyl 3-methoxy-4-[(5-nitroindazol-2-yl)methyl]benzoate. Preparation of5-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline Inlike manner to the preparation of6-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline,5-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline wasprepared from methyl 3-methoxy-4-[(5-nitroindazol-1-yl)methyl]benzoate.¹H NMR (DMSO-d₆): δ8.81 (d, 1H, J =2.3 Hz), 8.39 (s, 1H), 8.21 (dd, 1H,J =1.8 and 8.8 Hz), 7.87 (dd, 2H, J =3.6 and 8.8 Hz), 7.48 (d, 1H, J=1.2 Hz), 7.39 (dd, 1H, J =1.2 and 8.2 Hz), 7.33-7.15 (m, 3H), 6.85 (d,1H, J =8.2 Hz), 5.65 (s, 2H), 3.76 (s, 3H), 2.49 (s, 3H). Preparation of5-amino-1-[2-methoxy-4-(0-toluyl-sulfonamidocarboxy)benzyl]indazoline Inlike manner to the preparation of6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline,5-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline wasprepared by reduction of5-nitro-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline .¹H NMR (DMSO-d₆): δ7.87 (dd, 1H, J =1.2 and 7.7 Hz), 7.73 (s, 1H), 7.50(s, 1H), 7.35-7.14 (m, 5H), 6.78 (d, 1H, J =1.8 Hz), 6.75 (s, 1H), 6.53(d, 1H, J =8.2 Hz), 5.44 (s, 2H), 3.82 (s, 3H), 2.50 (s, 3H). 7.2.48Preparation of 8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine

7.3 Synthesis of 2,4-Pyrimidinediamines A variety of2,4-pyrimidinediamines of the invention were synthesized from the abovestarting materials and intermediates and other commercially availablereagents. Conditions suitable for synthesizingN2,N4-bis-substituted-2,4-pyrimidinediamine compounds (“generalSNAr”reaction conditions; Substitution Nucleophilic Aromatic Reaction)are exemplified with N2,N4-bis(4-ethoxyphenyl)-2,4-pyrimdinediamine(R926069) and N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R921218). Conditions suitable for synthesizing asymmetricN2,N4-disubstituted-2,4-pyrimdinediamines are exemplified byN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediame(R926210). 7.3.1 N2,N4-Bis(4-ethoxyphenyl)-2,4-pyrimidinediamine(R926069) To a solution of 2,4-dichloropyrimidine (0.015 g, 0.1 mmol) inEtOH (1 mL) was added 4-ethoxyaniline (0.034 g, 0.025 mmol) and heatedin a sealed tube at 70-80° C. for 24 h. Upon cooling the reaction wasdiluted with H₂O (10 mL), acidified with 2N HCl, the solid obtained wasfiltered, washed with H₂O and dried to giveN2,N4-bis(4-ethoxyphenyl)-2,4-pyrimidinediamine (R926069). ¹H NMR(CD₃OD): δ7.63 (d, 1H), 7.45 (d, 2H), J=9 Hz), 7.32 (d, 2H, J=9.3 Hz),6.95 (d, 2H, J=6.9 Hz), 6.87 (d, 2H, J=8.7 Hz), 6.23 (d, 1H, J=7.2 Hz),4.04 (m, 4H), 1.38 (m, 6H); LCMS: ret. time: 25.91 min.; purity: 99.5%;MS (m/e): 351 (MH⁺). 7.3.2N2,N4-Bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R921218) Amixture of 2,4-dichloro-5-fluoropyrimidine (0.0167 g, 0.1 mmol) and3-aminophenol (0.033 g, 0.3 mmol) in MeOH: H₂O (1.8:0.2 mL; v/v) wasshaken in a sealed tube at 100° C. for 24 h (or 80 oC for 3 days),cooled to room temperature, diluted with water (15 mL), acidified with2N HCl (pH >2). Upon saturation with sodium chloride it was extractedwith ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate andsolvent was removed. The resulting residue was filtered through a pad ofsilica gel (200-400 mesh) using CH₂Cl₂ - >1 >10% MeOH in CH₂Cl₂ toobtain the desiredN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R921218). Ifthe reaction scale is large enough, solid of the resulting product canbe isolated by filtration. ¹H NMR (CDCl₃): δ7.73 (d, 1H, J=5.1 Hz),7.12-6.90 (m, 6H), 6.64 (dd, 1H, J=1.8 and 8.1 Hz), 6.53 (dd, 1H, J=1.2and 5.7 Hz); LCMS: ret. time: 16.12 min.; purity: 100%; MS (m/e): 313(MH⁺). 7.3.3 N2,N4-Bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926017) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-methoxyaniline were reacted toyield N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ7.67 (d, 1H, J=4.8 Hz), 7.43 (d, 2H, J=9.3 Hz), 7.67 (d, 2H,J=8.7 Hz), 6.87 (d, 2H, J=9.6 Hz), 6.83 (d, 2H, J=8.7 Hz), 3.83 (s, 3H),3.81(s, 3H); LCMS: ret. time: 22.53 min.; purity: 100%; MS (m/e): 341(MH⁺). 7.3.4N2,N4-Bis(3-fluoro-4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926018) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-fluoro-4-trifluoromethylanilinewere reacted to yieldN2,N4-bis(3-fluoro-4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹HNMR (CDCl₃): δ8.01 (d, 1H, J=3 Hz), 7.77 (m, 3H), 7.61 (dt, 1H, J=4.2and 3 Hz), 7.20 (t, 1H, 8.7 Hz), 7.12 (t, 1H, J=9.3 Hz), 6.95 (s, 1H),6.82 (s, 1H); ¹⁹F NMR (CDCl₃): δ-17505 (s, 3F), -17517 (s, 3F), -17525(s, F), -17537 (s, F), -46835 (s, 1F); LCMS: ret. time: 32.39 min.;purity: 95%, MS (m/e): 453 (MH⁺). 7.3.5N2,N4-Bis(3,4-tetrafluoroethylendioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926037) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4-tetrafluoroethylenedioxyanilinewere reacted to yieldN2,N4-bis(3,4-tetrafluoroethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.01 (d, 1H, J=3.0 Hz), 7.71 (d, 1H, J=2.4 Hz), 7.70(1H, d, J=2.4 Hz), 7.18 (dd, 2H, J=2.4 and 6 Hz), 7.07 (d, 2H, J=1.8Hz), 7.00 (1H, bs), 6.81 (d, 1H, J=2.7 Hz); ¹⁹F NMR (CDCl₃): -26029(sept, 8F), -46791 (s, C5-F); LCMS: ret. time: 38.20 min.; purity: 85%;MS (m/e): 541 (MH⁺). 7.3.6N2,N4-Bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926038) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-trifluoromethoxyaniline werereacted to yieldN2,N4-bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ8.03 (bd, 1H), 7.62 (bs, 2H), 7.48 (bd, 1H), 7.39 (t, 1H,J=8.1 Hz), 7.34 (m, 1H), 7.29 (t, 1H, J=7.5 Hz), 7.01 (m, 2H), 6.88 (m,2H); ¹⁹F NMR (CDCl₃): -16447 (s, 3F), -16459 (s, 3F), -46738 (s, 1F);LCMS: ret. time: 33.77 min.; purity: 93%; MS (m/e): 449 (MH⁺). 7.3.7N2,N4-Bis(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926039) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-trifluoromethylanilinewere reacted to yieldN2,N4-bis(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.05 (bs, 1H), 7.89 (bd, 1H), 7.77 (dd, 1H, J=2.4 and 9Hz), 7.65 (dd, 1H, J=2.4 and 8.7 Hz), 7.49 (d, J=8.1 Hz), 7.40 (d, 1H,J=6.2 Hz), 7.03 (s, 1H), 6.91 (s, 1H); ¹⁹F NMR (CDCl₃): δ-17864 (s, 3F),-17894 (s, 3F), -46550 (s, 1F); LCMS: ret. time: 38.81 min.; purity:75%; MS (m/e): 485 (MH⁺). 7.3.8N2,N4-Bis(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926064) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-ethoxyaniline were reacted toyield N2,N4-bis(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ7.96 (1H, d, J=4.8 Hz), 7.22 (m, 6H), 7.07 (t, 1H, J=1.8 Hz),6.95 (dt, 1H, J=1.2 and 7.2 Hz), 6.77 (m, 2H), 3.88 (q, 4H, J=6.3 Hz),1.33 (two t, 6H, J=6.3 Hz); ¹⁹F NMR (CDCl₃): - 46175; LCMS: ret. time:26.86 min.; purity: 97%; MS (m/e): 369 (MH⁺). 7.3.9N2,N4-Bis(3-hydroxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926339) In like manner to toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methoxylaniline werereacted to yieldN2,N4-bis(3-hydroxy-4-methoxyphenyl)-5-fluoro--2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ7.82 (d, 1H J=4 Hz), 7.18 (m, 2H), 6.95 (m, 2H), 6.83 (m,2H) 3.93 (s, 6H); LCMS: ret. time: 16.63 min.; purity: 97 %; MS (m/e):373 (MH⁺). 7.3.10N2,N4-Bis(4-ethoxycarbonylamino-3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926340) In like manner to toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and4-ethoxycarbonylamino-3-hydroxyaniline were reacted to yieldN2,N4-bis(4-ethoxycarbonylamino-3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.86 (d, 1H J=4 Hz), 7.67 (m, 2H), 7.20 (dd, 1H, J=8Hz, J=4.1 Hz), 7.13 (d, 1H), 6.90 (m, 2H), 4.2(m, 4H), 1.32 (m, 6H);LCMS: ret. time: 20.92 min.; purity: 98 %; MS (m/e): 487 (MH⁺). 7.3.11N2,N4-Bis(-3-hydroxy-4-methylphenyl)-5-fluoro-2,4-pyrimidinediaminediamine(R926341) In like manner toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methylaniline werereacted to yieldN2,N4-bis(-3-hydroxy-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ7.83 (d, 1H J=4 Hz), 7.11 (m, 4H), 6.81 (m, 2H), 2.19 (m,6H); LCMS: ret. time: 20.69 min.; purity: 98 %; MS (m/e): 341 (MH⁺).7.3.12N2,N4-Bis[4-(2-methoxyethyleneoxy)phenyl]-5-fluoro--2,4-pyrimidinediamine(R926342) In like manner toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-(2-methoxyethyloxy)aniline werereacted to yieldN2,N4-bis[4-(2-methoxyethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.89 (d, 1H J=4 Hz), 7.54 (dd, 2H, J=6.8 and 2.7 Hz),7.38 (dd, 2H, J=6.8 and 2.7 Hz), 6.87 (dd, 2H, J=6.8 and 2.7 Hz), 6.82(dd, 2H, J=6.8 and 2.7 Hz) 4.6 (m, 4H), 4.11 (m, 4H), 3.35 (m, 6H);LCMS: ret. time: 21.76 min.; purity: 97 %; MS (m/e): 429 (MH⁺). 7.3.13N2,N4-Bis(dihydrobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminediamine(R909237) In like manner toN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-2,3-dihydrobenzofuran werereacted to yieldN2,N4-bis(dihydrobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminediamine.¹H NMR (CD₃OD): δ7.99 (d, 1H J=4 Hz), 7.22 (m, 4H), 6.81 (m, 2H), 4.55(m, 4H), 3.22 (m, 4H); LCMS: ret. time: 23.80 min.; purity: 98 %; MS(m/e): 438 (MH⁺). 7.3.14N2,N4-Bis(3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926065) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-methoxyaniline were reacted toyield N2,N4-bis(3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ7.96 (d, 1H, J=5.4 Hz), 7.24 (m, 6H), 7.06 (t, 1H, J=2.4 Hz),7.00 (dt, 1H, J=1.2 Hz), 6.79 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H); ¹⁹FNMR (CD₃OD): δ- 46112; LCMS: ret. time: 23.46 min.; purity: 99%; MS(m/e): 341 (MH⁺). 7.3.15N2,N4-Bis[4-(N,N-dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926086) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-N,N-dimethylaniline were reactedto yieldN2,N4-bis[4-(N,N-dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.84 (d, 1H, J=3.6 Hz), 7.43 (d, 2H, J=8.7 Hz), 7.34(d, 2H, J=8.7 Hz), 7.25 (s, 1H), 6.73 (m, 4H), 6.55 (s, 1H), 2.95 (s,6H), 2.90 (s, 6H); ¹⁹F NMR (CDCl₃): - 47770; LCMS: ret. time: 12.48min.; purity: 99%; MS (m/e): 367 (MH⁺). 7.3.16N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926109) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4-ethylenedioxyaniline werereacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ7.88 (d, 1H, J=3.6 Hz), 7.23 (d, 1H, J=2.3 Hz), 7.15 (d,1H, J=2.4 Hz), 7.00 (dd, 1H, J=3 and 8.1 Hz), 6.98 (dd, 1H, J=3 and 8Hz), 6.83 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=8.7 17Hz), 6.7(s, 1H), 6.58(s, 1H), 4.23 (m, 4H), 4.24(m, 4H); ¹⁹F NMR (CDCl₃): δ- 47445; LCMS:ret. time: 21.81 min.; purity: 96%; MS (m/e): 397 (MH⁺). 7.3.17N2,N4-Bis(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926110)In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4-dimethoxyaniline were reacted toyield N2,N4-bis(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ7.90 (d, 1H, J=1.8 Hz), 7.13 (d, 2H, J=4.8 Hz), 7.08 (d,1H, J=8.7 Hz), 6.94 (d, 2H, J=10.5 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.76 (d,1H, J=8.7 Hz), 6.70 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H),3..71 (s, 3H); ¹⁹F NMR (CDCl₃): δ- 47433; LCMS: ret. time: 19.64 min.;purity: 95%; MS (m/e): 401 (MH⁺). 7.3.18N2,N4-Bis[4-(N-morpholino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926114) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-N-morpholinylaniline were reactedto yieldN2,N4-bis[4-N-morpholinyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ7.80 (s, 1H), 7.78 (s, 1H, partially exchanged), 7.76 (bs, 1H,partially exchanged), 7.53 (d, 2H, J=8.1 Hz), 7.39 (d, 2H, J=9 Hz), 6.93(d, 2H, J=8.7 Hz), 6.86 (bd, 2H), 3.84 (m, 8H), 3.11 (m, 8H); ¹⁹F NMR(CD₃OD): δ- 47697; LCMS: ret. time: 18.15 min.; purity: 99.55%; MS(m/e): 451 (MH⁺). 7.3.19N2,N4-Bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R926206) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-chloroaniline were reacted toyield N2,N4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃ + CD₃OD): δ7.80 (d, 1H, J=4.2 Hz), 7.45 (d, 2H, J=8.7 Hz), 7.33(d, 2H, J=9 Hz), 7.20 (d, 2H, J=8.7 Hz), 7.14 (d, 2H, J=9.6 Hz); LCMS:ret. time: 28.84 min.; purity: 87%; MS (m/e): 349 (MH⁺). 7.3.20N2,N4-Bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R926209) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloroaniline were reacted toyield N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ8.08 (d, 1H, J=5.4 Hz), 7.70 (t, 1H, J=1.8 Hz), 7.57 (t, 1H,J=1.2 Hz), 7.54 (m, 1H), 7.35 (m, 4H), 7.28 (t, 1H, J=1.8 Hz), 7.24 (m,1H), 7.22 (t, 1H, J=1.8 Hz); ¹⁹F NMR (CD₃OD): - 43631; LCMS: ret. time:28.99 min.; purity: 99%; MS (m/e): 349 (M⁺). 7.3.21N2,N4-Bis(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine (R926222)In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-tert-butylaniline were reacted toyield N2,N4-bis(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ7.77 (d, 1H, J=3.9 Hz), 7.47 (d, 2H, J=9Hz), 7.38 (m, 4H),7.30 (d, 2H, J=8.7 Hz), 1.34 (s, 9H), 1.32 (s, 9H); LCMS: ret. time:34.09 min.; purity: 93%; MS: 393 (MH⁺). 7.3.22N2,N4-Bis(3-chloro-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926223) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline werereacted to yieldN2,N4-bis(3-chloro-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃ + CD₃OD)): δ7.81 (d, 1H), 7.60 (m, 1H), 7.58 (m, 1H), 7.38(m, 1H), 7.19 (m, 1H), 7.0 (m, 2H); LCMS: ret. time: 28.98 min.; purity:97%; MS (m/e): 385 (M⁺). 7.3.23N2,N4-Bis(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine (R926224) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-fluoroaniline were reacted toyield N2,N4-bis(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ8.79 (d, 2H, J=5.4 Hz), 7.40 (m, 2H), 7.30 (m, 2H), 6.90 (m,4H); ¹⁹NMR (CDCl₃): - 32425 (s, 1F), -32940 (s, 1F), -45525 (s, 1F);LCMS: ret. time: 23.53 min.; purity: 100%; MS (m/e): 317 (MH⁺). 7.3.24N2,N4-Bis(4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (R926225) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-methylaniline were reacted toyield N2,N4-bis(4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ7.73 (d, 1H, J=4.2 Hz), 7.43 (d, 2H, J=8.1 Hz), 7.36 (d, 2H,J=8.4 Hz), 7.14 (d, 2H, J=8.4 Hz), 7.10 (d, 2H, J=8.1 Hz), 2.39 (s, 3H),2.35 (s, 3H); LCMS: ret. time: 25.81 min.; purity: 99.65%; MS (m/e): 309(MH⁺). 7.3.25N2,N4-Bis[(4-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926240) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and ethyl 4-aminophenoxyacetate werereacted to yieldN2,N4-bis[(4-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.8 (bs, 1H), 7.50 (d, 2H, J=9.3 Hz), 7.32 (d, 2H,J=8.41 Hz), 6.88 (m, 4H), 4.72 (s, 2H), 4.70 (s, 2H), 3.79 (s, 3H), 3.78(s, 3H); ¹⁹F NMR (CDCl₃): -47570; LCMS: ret. time: 21.17 min.; purity:95%; MS (m/e): 457 (MH⁺). 7.3.26(±)-N2,N4-Bis[4-methoxycarbonyl(α-methyl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R926254) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and (±)-ethyl2-(4-aminophenoxy)propionate were reacted to yield(±)-N2,N4-bis[4-methoxycarbonyl(α-methyl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.89 (bs, 1H), 7.48 (dd, 2H, J=2.4 and 6.9 Hz), 7.40(dd, 2H, J=1.8 and 6.9 Hz), 6.85 (m, 4H), 6.76 (s, 1H), 6.63 (s, 1H),4.75 (hex, 2H, J=6.3 Hz), 3.77 (s, 3H), 3.76 (s, 3H), 1.62 (t, 6H, J=7.5Hz); LCMS: ret. time: 23.76 min.; purity: 97%; MS (m/e): 485 (MH+).7.3.27N2,N4-Bis[(3-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926255) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and ethyl 3-aminophenoxyacetate werereacted to yieldN2,N4-bis[(3-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.96 (d, 1H, J=2.4 Hz), 7.71 (t, 1H, J=2.4 Hz), 7.44(m, 2H), 7.21 (m, 3H), 6.96 (dd, 1H, J=1.2 and 7.8 Hz), 6.86 (d, 1H, J=3Hz), 6.53 (m, 1H), 4.64 (s, 2H), 4.60 (s, 2H), 3.79 (s, 6H); LCMS: ret.time: 21.72 min.; purity: 87%; MS (m/e): 457 (MH⁺). 7.3.28N2,N4-Bis(3-acetyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926387) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-acetoxyaniline were reacted toyield N2,N4-bis[(3-acetoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.Alternatively,N2,N4-bis[(3-acetoxyphenyl]-5-fluoro-2,4-pyrimidinediamine can beprepared by acetylation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine with acetylchloride in the presence of pyridine in CH₂Cl₂. ¹H NMR (CDCl₃): δ8.00(bs, 1H), 7.51-7.25 (m, 8H), 2.32 (s, 3H), 2.28 (s, 3H); LCMS: ret.time: 22.14 min; purity: 100%; MS (m/e): 397 (MH⁺). 7.3.29N2,N4-Bis(3-benzyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926394) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-benzyloxyaniline were reacted toyield N2,N4-bis(3-benzyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ7.98 (bs, 1H), 7.42-6.99 (m, 16H), 6.75 (d, 1H, J=2.4 Hz),6.71 (m, 1H), 6.60 (dd, 1H, J=2.4 and 8.4 Hz), 6.32 (m, 1H), 4.97 (s,2H), 4.94 (s, 2H); LCMS: ret. time: 32.56 min.; purity: 98%; MS (m/e):493 (MH⁺). 7.3.30N2,N4-Bis(2-phenylphenyl)-5-fluoro-2,4-pyrimidinediamine (R926398) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-phenylaniline were reacted toyield N2,N4-bis[(2-phenylphenyl]-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ8.35 (m, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.45-7.00 (m, 18H);LCMS: ret. time: 30.29 min.; purity: 68%; MS (m/e): 433 (MH⁺). 7.3.31(R926404) N2, N4-Bis(2-phenylphenyl)-5-methyl-2,4-pyrimidinediamine Inlike manner to the preparation of5-fluoro-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-aminobiphenyl and 2,4-dichloro-5-methylpyrimidine were reacted toprovide N2, N4-bis(2-phenylphenyl)-5-methyl-2,4-pyrimidinediamine. LCMS:ret. time: 30.47 min.; purity: 91%; MS (m/e): 429 (MH⁺). 7.3.32N2,N4-Bis[(4-methoxy-3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926399) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-methoxy-3-phenylaniline werereacted to yieldN2,N4-bis[(4-methoxy-3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ7.83 (d, 1H, J=4.2 Hz), 7.57 (bd, 1H, J=8.7 Hz), 7.48 (d,1H, J=2.7 Hz), 7.47-7.22 (m, 12H), 6.85 (d, 1H, J=8.7 Hz), 6.78 (d, 1H,9.3 Hz), 3.72 (s, 3H), 3.69 (s, 3H); LCMS: ret. time: 29.97 min.;purity: 92%; MS (m/e): 493 (MH⁺). 7.3.33N2,N4-Bis[(2-methoxy-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926400) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methoxy-5-phenylaniline werereacted to yieldN2,N4-bis[(2-methoxy-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ8.03 (d, 1H, J=6.6 Hz), 7.76 (t, 1H, J=2.4 Hz), 7.28-7.10(m, 13H), 7.07 (d, 1H, J=9 Hz), 7.01 (d, 1H, J=8.1 Hz), 3.91 (s, 3H),3.86 (s, 3H); LCMS: ret. time: 18.58 min.; purity: 96%; MS (m/e): MH⁺).7.3.34N2,N4-Bis[(2-methoxy-5-methyl-4-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926401) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methoxy-5-methyl-4-phenylanilinewere reacted to yieldN2,N4-bis[(2-methoxy-5-methyl-4-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.00 (d, 1H, J=4.8 Hz), 7.73 (s, 1H), 7.66 (s, 1H),7.43-7.24 (m, 9H), 6.91 (s, 1H), 6.82 (s, 1H), 3.86 (s, 3H), 3.85 (s,3H), 2.14 (s, 3H), 1.99 (s, 3H); LCMS: ret. time: 19.98 min.; purity:99%; MS (m/e): 521 (MH⁺). 7.3.35N2,N4-Bis[(2-methyl-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926402) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methyl-5-phenylaniline werereacted to yieldN2,N4-bis[(2-methyl-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ7.84 (bd, 1H), 7.51-7.20 (m, 16H), 2.30 (s, 3H), 2.24 (s,3H); LCMS: ret. time: 18.57 min.; purity: 87%; MS (m/e): 461 (MH⁺).7.3.36 N2,N4-Bis[(3-phenyl)phenyl]--5-fluoro-2,4-pyrimidinediamine(R926403) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-phenylaniline were reacted toyield N2,N4-bis[(3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ8.02 (d, 1H, J=5.1 Hz), 7.82 (t, 1H, J=1.5 Hz), 7.67 (t, 1H,J=1.8 Hz), 7.58 (dd, 1H, J=1.2 and 7.2 Hz), 7.42-7.24 (m, 15H); LCMS:ret. time: 32.06 min.; purity: 94%; MS (m/e): 433 (MH⁺). 7.3.37N2,N4-Bis(4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926405) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-acetoxyaniline were reacted toyield N2,N4-bis[(4-hydroxyphenyl]-5-fluoro-2,4-pyrimidinediamine. Afterthe work up it was observed that the acetoxy group was hydrolyzed toafford the N2,N4-bis(4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamineinstead of the corresponding acetate derivative. ¹H NMR (CD₃OD): δ7.74(d, 1H, J=5.6 Hz), 7.43 (dd, 2H, J=2.1 and 6.6 Hz), 7.28 (dd, 2H, J=2.4and 6.3 Hz), 6.74 (dd, 2H, J=2.4 and 6.3 Hz), 6.66 (dd, 2H, J=2.4 and7.2 Hz); ¹⁹F NMR (CD₃OD): - 48116 (d, 1F); LCMS: ret. time: 16.15 min;purity: 100%; MS (m/e): 313 (MH⁺). 7.3.38N2,N4′-Bis(4-hydroxy-3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926469) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-hydroxy-3-methylaniline werereacted to yieldN2,N4-bis[(4-hydroxy-3-methylphenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ7.64 (d, 1H, J=3.6 Hz), 7.11 (t, 2H, J=9 Hz), 6.70-6.45(m, 4H), 2.15 (s, 3H), 2.09 (s, 3H); ¹⁹F NMR (CD₃OD): - 46278; LCMS:ret. time: 15.53; purity: 84%; MS (m/e): 341 (MH⁺). 7.3.39N2,N4-Bis[4-(tert-butoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926574) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and tert-butyl 4-aminophenoxyacetatewere reacted to yieldN2,N4-bis[4-(tert-butoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine¹H NMR (CDCl₃): δ7.88 (s, 1H), 7.48 (d, 2H, J=8.4 Hz), 7.40 (d, 2H,J=8.7 Hz), 6.86 (m, 4H), 4.52 (s, 2H), 4.48 (s, 2H), 1.49 (s, 9H), 1.48(s, 9H); LCMS: ret. time: 28.48 min.; purity: 95%; MS (m/e): 541 (MH⁺).7.3.40 N2,N4-Bis(indol-5-yl)-5-fluoro-2,4-pyrimidinediamine (R926582) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-aminoindole were reacted to yieldN2,N4-bis(indol-5-yl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time:20.26 min.; purity: 99%; MS (m/e): 359 (MH⁺). 7.3.41N2,N4-Bis(4-cyanomethylphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926319) In like manner toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and 4-cyanomethylaniline werereacted to yieldN2,N4-bis(4-cyanomethylphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.72 (s, 1H), 7.64 (m, 4H), 7.32 (d, 2H, J=8.7 Hz),7.21 (d, 2H, J=8.4 Hz), 4.3 (q, 2H, J=7.0 Hz), 3.97 (s, 2H,), 3.89 (s,2H), 1.32 (3H, J=7 Hz); LCMS: ret. time: 30.83 min.; purity: 90 %; MS(m/e): 413 (MH⁺). 7.3.42N2,N4-Bis(3-indazol-6-yl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926320) In like manner toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and 6-aminoindazole were reactedto yield N2,N4-bis(6-indazolyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.76 (s, 1H), 7.73(d, 2H J=8.8), 7.54 (m, 4H), 7.36(d, 2H, J=9.5 Hz), 4.3 (q, 2H, J=7.0 Hz), 1.34 (3H, J=7 Hz); LCMS: ret.time 27.59 min.; purity: 95 %; MS (m/e): 415 (MH⁺). 7.3.43N2,N4-Bis(3-indazol-7-yl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926321) In like manner toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and 7-aminoindazole were reactedto yield N2,N4-bis(7-indazolyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.70 (s, 1H), 7.54 (d, 2H J=8.4 Hz), 7.37 (m, 6H),4.3 (q, 2H, J=7.0 Hz), 1.33 (3H, J=7 Hz); LCMS: ret. time 23.61 min.;purity: 94 %; MS (m/e): 415 (MH⁺). 7.3.44N2,N4-Bis[6-(1,4-benzoxazine-3-onyl)]-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926325) In like manner to toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and6-amino-1,4-benzoxazine-3-one were reacted to yieldN2,N4-bis[6-(1,4-benzoxazine-3-onyl)]-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.66 (s, 1H), 7.21 (dd, 2H J=8.8 and J=2.2 Hz), 6.89(d, 2H J=8.4 Hz), 4.54 (s, 2H) 4.49 (s, 2H) 4.3 (q, 2H, J=7.0 Hz), 1.33(3H, J=7 Hz); LCMS: ret. time 23.08 min.; purity: 88 %; MS (m/e): 477(MH⁺). 7.3.45N2,N4-Bis(4-ethoxycarbonylmethyleneaminophenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926331) In like manner to toN2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine,2,4-dichloro-5-ethoxycarbonylpyrimidine and4-ethoxycarbonylmethyleneaminoaniline were reacted toyieldN2,N4-bis(4-ethoxycarbonylaminophenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.72 (s, 1H), 7.70 (d, 2H J=8.8 Hz), 7.28 (d, 2H J=8.4Hz), 7.05 (d, 2H, J=8.4 Hz) 6.82 (d, 2H J=8.4 Hz) 4.5 (m, 4H), 4.23 (m,6H) 1.53 (m, 9H); LCMS: ret. time 18.08 min.; purity: 85%; MS (m/e): 537(MH⁺). 7.3.46N2,N4-Bis(4-ethoxyphenyl)-6-methoxycarbonyl-2,4-pyrimidinediamine(R926058) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-6-methoxycarbonylpyrimidine with 4-ethoxyaniline gaveN2,N4-bis(4-ethoxyphenyl)-6-methoxycarbonyl-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ7.42 (bs, 1H), 7.35 (bd, 4H), 6.85 (bs, 1H), 6.75 (bd,4H), 3.97 (q, 4H, J=4.8 Hz), 3.92 (s, 3H), 1.36 (t, 6H, J=6.3 Hz); LCMS:ret. time: 27.47 min.; purity: 97%; MS (m/e): 409 (MH⁺). 7.3.47N2,N4-Bis(4-ethoxyphenyl)-5-methyl-2,4-pyrimidinediamine (R926068) In amanner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with 4-ethoxyaniline gaveN2,N4-bis(4-ethoxyphenyl)-5-methyl-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ7.55 (s, 1H), 7.40 (d, 2H), 7.21 (d, 2H, J=8.7 Hz), 6.90 (dd,4H, J=8.7 Hz), 4.04 (q, 4H, J=6.6 Hz), 2.17 (m, 6H); LCMS: ret. time:26.51 min.; purity: 95%; MS (m/e): 365 (MH⁺). 7.3.48N2,N4-Bis(4-ethoxyphenyl)-6-chloro-2,4-pyrimidinediamine (R926072) In amanner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4,6-trichloropyrimidine with 4-ethoxyaniline gaveN2,N4-bis(4-ethoxyphenyl)-6-chloro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ7.42 (d, 2H, J=9 Hz), 7.18 (d, 2H, J=8.7 Hz), 6.89 (d, 2H,J=6.3 Hz), 6.84 (d, 2H, J=8.7 Hz), 6.58 (bs, 1H), 4.02 (m, 4H), 1.43 (m,6H); LCMS: ret. time: 83.21 min.; purity: 87%; MS (m/e): 385 (MH⁺).7.3.49 N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-methyl-2,4-pyrimidinediamine(R926242) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with 3,4-ethyleneoxyaniline gaveN2,N4-bis(3,4-ethylenedioxyphenyl)-5-methyl-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ7.75 (bs, 1H), 7.06 (d, 1H, J=2.4 Hz), 6.96 (d, 1H, J=2.1Hz), 6.94 (d, 1H, J=2.1 Hz), 6.85-6.77 (m, 2H), 6.70 (d, 1H, J=9 Hz),4.23 (s, 4H), 4.19 (s, 4H), 2.09 (s, 3H); LCMS: ret. time: 22.01 min.;purity: 100%; MS (m/e): 393 (MH⁺). 7.3.50N2,N4-Bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine (R926243) In amanner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloropyrimidine with 3,4-ethyleneoxyaniline gaveN2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ10.95 (s, 1H), 10.50 (s, 1H), 7.84 (bd, 2H), 7.24 (bd, 2H),6.79 (bd, 2H), 6.40 (bd, 2H), 4.24 (s, 8H); LCMS: ret. time: 21.68 min.;purity: 100%; MS (m/e): 379 (MH⁺). 7.3.51N2,N4-Bis(3-hydroxyphenyl)-5-methyl-2,4-pyrimidinediamine (R926248) In amanner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with 3-hydroxyaniline gaveN2,N4-bis(3-hydroxyphenyl)-5-methyl-2,4-pyrimidinediamine. LCMS: ret.time: 16.76 min.; purity: 100%, MS (m/e): 309 (MH⁺). 7.3.52 N2,N4-Bis(3-hydroxyphenyl)-2,4-pyrimidinediamine (R926249) In a manneranalogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloropyrimidine with 3-hydroxyaniline gaveN2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 16.21min.; purity: 100%; MS (m/e): 295 (MH⁺). 7.3.53N2,N4-Bis[(4-methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R926256) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloropyrimidine with methyl 4-aminophenoxyacetate gaveN2,N4-bis[(4-methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.7 (bs, 1H), 10.28 (bs, 1H), 7.84 (d, 1H, J=6.9Hz), 7.48 (bd, 2H), 7.35 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=9 Hz), 6.90(d, 2H, J=8.7 Hz), 6.35 (d, 1H, J=6.9 Hz), 4.81 (s, 2H), 4.79 (s, 2H),3.69 (s, 3H), 3.68 (s, 3H); LCMS: ret. time: 21.27 min.; purity: 98%; MS(m/e): 439 (MH⁺). 7.3.54(±)-N2,N4-Bis[4-methoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R926257) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloropyrimidine with (±)-methyl 2-(4-aminophenoxy)propionategave(±)-N2,N4-bis[4-methoxycarbonyl(alpha-methyl)methyleneoxyoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 24.09 min.; purity: 90%; MS (m/e): 467 (MH⁺). 7.3.55N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-5-methyl-2,4-pyrimidinediamine(R926258) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with methyl-4-aminophenoxyacetategaveN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-5-methyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.21 (s, 1H), 9.65 (s, 1H), 7.78 (s, 1H), 7.42 (dd,2H), J=2.7 and 8.7 Hz), 7.28 (dd, 2H, J=8.1 Hz), 6.94 (d, 2H, J=8.47Hz), 6.85 (d, 2H, J=8.7 Hz), 4.82 (s, 2H), 4.77 (s, 2H), 3.69 (s, 3H),3.68 (s, 3H), 2.12 (s, 3H); LCMS: ret. time: 21.76 min.; purity: 100%;MS (m/e): 453 (MH⁺). 7.3.56(±)-N2,N4-Bis[4-ethoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-5-methyl-2,4-pyrimidinediamine(R926259) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with (±)-ethyl2-(4-aminophenoxy)propionate gave(±)-N2,N4-bis[4-ethoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-5-methyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.9 (bs, 1H), 9.35 (bs, 1H), 7.79 (s, 1H), 7.43 (dd,2H, J=3.6 and 8.7 Hz), 7.32 (d, 2H, J=7.5 Hz), 6.86 (d, 2H, J=9 Hz),6.78 (d, 2H, J=8.7 Hz), 4.95 (q, 1H, J=7.2 Hz), 4.90 (q, 1H, J=7.2 Hz),4.12 (2q, 4H, J=5.7 Hz), 2.10 (s, 3H), 1.51 (d, 3H, J=6.3 Hz), 1.47 (d,3H, J=6.3 Hz), 1.16 (2t, 6H, J=5.7 Hz); LCMS: ret. time: 27.41 min.;purity: 96%; MS (m/e): 509 (MH⁺). 7.3.57N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-methyl-2,4-pyrimidinediamine(R926397) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-methylpyrimidine with 2-(4-hydroxyphenyl)ethylaminegave N2,N4-bis[2-(4-hydroxyphenyl)ethyl]-5-methyl-2,4-pyrimidinediamine.LCMS: ret. time: 19.94 min.; purity: 100%; MS (m/e): 365 (MH⁺). 7.3.58N2,N4-Bis-(3,4-dimethoxypenyl)-5-nitro-2,4-pyrimidinediamine (R940089)In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with 3,4-dimethoxyaniline gaveN2,N4-bis-(3,4-dimethoxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS:ret. time: 28.30 min.; purity: 100%; MS (m/e): 428 (MH⁺); ¹H NMR(CDCl₃): δ10.30 (1H, s), 9.14 (1H, s), 7.52 (1H, s), 7.08 (3H, m), 7.00(1H, d, J=8.4 Hz), 6.84 (1H, d, J=8.4 Hz), 6.76 (1H, d, J=8.4 Hz), 3.90(3H, s), 3.87 (3H, s), 3.68 (3H, s), 3.60 (3H, s). 7.3.59N2,N4-Bis-(4-ethoxypenyl)-5-nitro-2,4-pyrimidinediamine (R940090) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with 4-ethoxyaniline gaveN2,N4-bis-(4-ethoxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS: ret.time: 35.91 min.; purity: 100%; MS (m/e): 396 (MH⁺); ¹H NMR (CDCl₃):δ10.25 (1H, s), 9.11 (1H, s), 7.44 (2H, d, J=8.6 Hz), 7.37 (2H, d,J=9Hz), 6.88 (2H, d, J=8.6 Hz), 6.80 (2H, d, J=8.6 Hz), 4.06 (2H, q,J=7.2 Hz), 4.02 (2H, q, J=7.2 Hz), 1.45 (3H, t, J=7.2 Hz), 1.42 (3H, t,J=7.2 Hz). 7.3.60N2,N4-Bis-(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine(R940095) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with 3,4-ethylenedioxyaniline gaveN2,N4-bis-(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS:ret. time: 30.78 min.; purity: 100%; MS (m/e): 424 (MH⁺); ¹H NMR(CDCl₃): δ10.21 (1H, s), 9.10 (1H, s), 7.40 (1H, s), 7.11-6.71 (6H, m),4.29 (4H, s), 4.25 (4H, s). 7.3.61N2,N4-Bis-[(4-ethoxycarbonylmethyleneoxy)phenyl]-5-nitro-2,4-pyrimidinediamine(R940096) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with ethyl-4-aminophenoxyacetate gaveN2,N4-bis-[(4-ethoxycarbonylmethyleneoxy)phenyl]-5-nitro-2,4-pyrimidinediamine.LCMS: ret. time: 32.48 min.; purity: 94%; MS (m/e): 512 (MH⁺); 1H NMR(CDCl₃): δ10.22 (1H, s), 9.13 (1H, s), 7.50 (1H, s), 7.45 (2H, d, J=8.7Hz), 7.38 (2H, d, J=8.7 Hz), 6.93 (2H, d, J=8.7 Hz), 6.83 (2H, d, J=8.7Hz), 4.67 (2H, s), 4.63 (2H, s), 4.29 (2H, q, J=7.2 Hz, 4.28 (2H, q,J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz), 1.30 (3H, t, J=7.2 Hz). 7.3.62N2,N4-Bis-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-nitro-2,4-pyrimidinediamine(R940100) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-nitropyrimidine with2,2-difluoro-5-amino-1,3-benzodioxole gaveN2,N4-bis-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-nitro-2,4-pyrimidinediamine.LCMS: ret. time: 38.15 min.; purity: 96%; MS (m/e): 467 (M⁺); ¹H NMR(CDCl₃): δ10.76 (1H, s), 10.49 (1H, s), 9.20 (1H, s), 7.74 (2H, s), 7.56(1H, d, J=11.4 Hz), 7.33 (2H, m), 7.20 (1H, m). 7.3.63N2,N4-Bis-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940215) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with 3,5-dichloro-4-hydroxyanilinegaveN2,N4-bis-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 21.26 min.; purity: 88%; MS (m/e): 450 (M⁺); ¹H NMR(DMSO-d₆): δ9.96 (1H, s), 9.59 (1H, s), 9.47 (1H, s), 9.37 (1H, s), 8.22(1H, d, J=3.6 Hz), 7.79 (2H, s), 7.74 (2H, s). 7.3.64N2,N4-Bis-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R940216) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with3-chloro-4-hydroxy-5-methylaniline gaveN2,N4-bis-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.55 min.; purity: 99%; MS (m/e): 410 (MH⁺); ¹H NMR(DMSO-d₆): δ9.23 (1H, s), 9.07 (1H, s), 8.99 (1H, s), 8.66 (1H, s), 8.13(1H, d, J=3.6 Hz), 7.59 (2H, t, J=3.1 Hz), 7.50 (1H, d, J=2.3 Hz), 7.34(1H, d, J=2.3 Hz), 2.27 (3H, s), 2.18 (3H, s). 7.3.65N2,N4-Bis-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940217) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with 2,3-dimethyl-4-hydroxyanilinegaveN2,N4-bis-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 19.07 min.; purity: 99%; MS (m/e): 369 (MH⁺); ¹H NMR(DMSO-d₆): δ9.21 (1H, s), 8.99 (1H, s), 8.63 (1H, s), 7.92 (1H, s), 7.84(1H, d, J=3.6 Hz), 6.94 (1H, d, J=8.5 Hz), 6.85 (1H, d, J=8.5 Hz), 6.70(1H, d, J=8.5 Hz), 6.58 (1H, d, J=8.5 Hz), 2.12 (3H, s), 2.06 (3H, s),2.02 (3H, s), 1.94 (3H, s). 7.3.66N2,N4-Bis-(4-Acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine (R940222)In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with 4-acetamidoaniline gaveN2,N4-bis-(4-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret.time: 14.82 min.; purity: 95%; MS (m/e): 395 (MH⁺); ¹H NMR (DMSO-d₆):δ10.33 (1H, s), 10.14 (1H, s), 10.07 (2H, s), 8.39 (1H, d, J=5.1 Hz),7.64 (8H, m), 2.15 (3H, s), 2.13 (3H, s). 7.3.67N2,N4-Bis(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine R940297 Inlike manner to the preparation ofN2,N4-bis-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-isopropylaniline were reacted togive N2,N4-bis-(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 29.58 min.; Purity: 98 %; MS (m/e): 365 (MH⁺); ¹H NMR(DMSO-d₆): δ10.5 (1H, s), 10.34 (1H, s), 8.41 (1H, d, J=5.1 Hz), 7.62(1H, d, J=8.1 Hz), 7.53 (1H, s), 7.43 (1H, d, J=8.1 Hz), 7.37 (2H, m),7.29 (1H, t, J=8.1 Hz), 7.19 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=7.8 Hz),2.88 (2H, m), 1.25 (6H, d, J=7.2 Hz), 1.201 (6H, d, J=7.2 Hz). 7.3.68N2,N4-Bis(3,4,5-trimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926688) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4,5-trimethoxyaniline were reactedto yieldN2,N4-bis(3,4,5-trimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 19.55 min.; purity: 99 %; MS (m/e): 461 (MH⁺). 7.3.69N2,N4-Bis(2-methyl-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine R925800In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 5-phenyl-ortho-toluidine were reactedto yieldN2,N4-bis(2-methyl-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. LCMS:ret. time: 19.54 min.; purity: 90 %; MS (m/e): 422 (MH⁺). 7.3.70N2,N4-Bis(2-methoxy-5-methyl-4-phenylphenyl)-5-bromo-2,4-pyrimidinediamine(R925801) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine 5-methyl-4-phenyl-ortho-anisidine werereacted to yieldN2,N4-bis(2-methoxy-5-methyl-4-phenylphenyl)-5-bromo-2,4-pyrimidinediamine.LCMS: ret. time: 20.99 min.; purity: 85 %; MS (m/e): 583 (MH⁺). 7.3.71N2,N4-Bis(indol-6-yl)-5-fluoro-2,4-pyrimidinediamine (R926594) In likemanner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted to yieldN2,N4-bis(indol-6-yl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time:22.39 min.; purity: 85%; MS (m/e): 359 (MH⁺). 7.3.72N2,N4-Bis(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine (R926604) In like mannerto the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methoxycarbonyl-5-aminobenzofuranwere reacted to yield N2,N4-bis(2-methoxycarbonylbenzofuran-5-yl))-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ10.3 (bs, 1H), 10.05 (bs, 1H), 8.25 (d, 1H, J=5.4 Hz), 8.06 (s, 1H),7.94 (s, 1H), 7.77-7.49 (m, 5H), 7.36 (bs, 1H), 3.89 (s, 3H), 3.87 (s,3H). 7.3.73N2,N4-Bis[4-(methoxycarbonylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926605) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and ethyl 4-aminophenyl acetate werereacted to yieldN2,N4-bis[4-(methoxycarbonylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine.The cross esterification reaction of ethyl ester to obtain thecorresponding methyl ester was observed. ¹H NMR (CDCl₃): δ10.62 (s, 1H),8.06 (s, 1H), 7.69 (d, 1H, J=4.5 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.43 (d,2H, J=8.7 Hz), 7.30 (d, 2H, J=8.4 Hz), 7.20 (d, 2H, J=8.4 Hz), 3.73 (s,3H), 3.72 (s, 3H), 3.67 (s, 2H), 3.63 (s, 2H). 7.3.74N2,N4-Bis(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine(R926616) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-ethoxycarbonyl-5-indoleamine werereacted to yieldN2,N4-bis(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ11.83 (s, 1H), 11.63 (s, 1H), 9.21 (s, 1H), 8.99 (s,1H), 8.08 (s, 1H), 8.01 (m, 2H), 7.49-7.22 (m, 4H), 6.92 (s, 1H), 6.63(s, 1H), 4.29 (q, 4H, J=7.2 Hz), 1.32 (m, 6H); LCMS: ret. time: 24.74min.; purity: 99%; MS (m/e): 503 (MH⁺). 7.3.75N2,N4-Bis(coumarin-6-yl)-5-fluoro-2,4-pyrimidinediamine (R926617) Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 6-aminocoumarin were reacted toyield N2,N4-bis(coumarin-6-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ8.17 (d, 2H, J=3.6 Hz), 7.97-7.74 (m, 5H), 7.40 (1H, d,J=8.7 Hz), 7.30 (d, 1H, J=9Hz), 6.50 (d, 1H, J=10.2 Hz), 6.40 (d, 1H,J=9.3 Hz); LCMS: ret. time: 19.05 min.; purity: 94%; MS (m/e): 417(MH⁺). 7.3.76N2,N4-Bis(4-methoxymethyl)coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine(R926620) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 7-amino-4-methoxymethylcoumarin werereacted to yieldN2,N4-bis(coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ10.38 (s, 1H), 8.42 (d, 1H, J=3 Hz), 8.28 (m, 1H), 8.05-7.93(m, 2H), 7.77-7.50 (m, 4H), 6.31 (s, 1H), 6.29 (s, 1H), 4.66 (s, 2H),4.65 (s, 2H), 3.43 (s, 3H), 3,41 (s, 3H); LCMS: MS (m/e): 505 (MH⁺).7.3.77 N2,N4-Bis(3-(hydroxymethyl)phenyl)-5-fluoro-2,4-pyrimidinediamine(R925757) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-aminobenzylalcohol were reacted toyield N2,N4-bis(3-(hydroxymethyl)phenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.90 (d, 1H, J=3.3 Hz), 7.71 (m, 1H), 7.61 (d, 1H,J=6.9 Hz), 7.50 (d, 1H, J=6.0), 7.47 (s, 1H), 7.31 (t, 1H, J=8.1 Hz),7.22 (t, 1H, J=8.1 Hz), 7.10 (d, 1H, J=6.9), 6.97 (d, 1H, J=7.5 Hz),4.63 (s, 4H); LCMS: ret. time: 15.36 min.; purity: 100%; MS (m/e): 342(MH⁺). 7.3.78N2,N4-Bis[(2R)-hydroxy-(1S)-methyl-2-phenylethyl]-5-fluoro-2,4-pyrimidinediamine(R925767) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and (1R,2S)-(−)-norephedrine werereacted to yieldN2,N4-bis[(2R)-hydroxy-(1S)-methyl-2-phenylethyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ7.67 (s, 1H), 7.49-7.42 (m, 4H), 7.38-7.19 (m,6H), 6.09 (d, 1H, J=9.0 Hz), 5.73 (d, 1H, J=7.5 Hz), 5.61 (d, 1H, J=9.3Hz), 5.04 (d, 1H, J=3.6 Hz), 4.97 (d, 1H, J=2.7 Hz), 4.74 (bs, 1H), 4.48(bs, 1H), 4.30-4.25 (m, 1H), 1.09 (d, 1H, J=6.9 Hz), 1.03 (d, 1H, J=6.6Hz); LCMS: ret. time: 21.56 min.; purity: 98%; MS (m/e): 397(MH⁺).7.3.79 N2,N4-Bis(2-hydroxy-2-phenylethyl)-5-fluoro-2,4-pyrimidinediamine(R925768) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-amino-1-phenylethanol were reactedto yieldN2,N4-bis(2-hydroxy-2-phenylethyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (acetone-d₆): δ8.15 (s, 1H), 7.46-7.22 (m, 10H), 5.01 (dd, 1H), 4.91(dd, 1H), 4.78 (dd, 1H), 3.86-3.18 (m, 5H); LCMS: ret. time: 19.64 min.;purity: 89 %; MS (m/e): 369 (MH⁺). 7.3.80N2,N4-Bis(furfuryl)-5-fluoro-2,4-pyrimidinediamine (R925769) In a mannersimilar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and furfurylamine were reacted to yieldN2,N4-bis(furfuryl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (CDCl₃):δ7.72 (bs, 1H), 7.38 (dd, 2H, J=1.8 and 7.5 Hz), 6.34-6.30 (m, 2H), 6.22(dd, 2H, J=2.4 and 9.9 Hz), 5.163 (bs, 2H), 4.63 (d, 2H, J=6.0), 4.54(d, 2H, J=6.0).; ¹⁹F NMR (CDCl₃): - 48621; LCMS: ret. time: 97.27min.;purity: 97%; MS (m/e): 289 (MH⁺). 7.3.81N2,N4-Bis(piperonyl)-5-fluoro-2,4-pyrimidineamine (R925770) In a mannersimilar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and piperonylamine were reacted to yieldN2,N4-bis(piperonyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (CDCl₃):δ7.60 (bs, 1H), 6.78-6.69 (m, 6H), 5.93 (s, 2H), 5.91 (s, 2H), 4.51 (d,2H, J=5.7 Hz), 4.43 (d, 2H, J=5.1 Hz); ¹⁹F NMR (CDCl₃): - 45257; LCMS:ret. time: 22.06 min.; purity: 96%; MS (m/e): 397 (MH⁺). 7.3.82N2,N4-Dibenzyl-5-fluoro-2,4-pyrimidinediamine (R925772) In a mannersimilar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and benzylamine were reacted to yieldN2,N4-bis(benzyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ7.69(bs, 1H), 7.35-7.24 (m, 10H), 5.63 (bs, 1H), 5.27 (bs, 1H), 4.61 (d, 2H,J=6.0 Hz), 4.55 (d, 2H, J=6.0 Hz); ¹⁹F NMR (CDCl₃): - 48580; LCMS: ret.time: 23.73 min.; purity: 100%; MS (m/e): 309 (MH⁺). 7.3.83N2,N4-Bis(3,4-methylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925776) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3,4-methylenedioxyaniline werereacted to yieldN2,N4-bis(3,4-methylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ7.86 (bs, 1H), 7.27 (m, 1H), 7.19 (m, 1H), 6.89 (dd, 2H,J=2.1 and 8.1 Hz), 6.80 (dd, 2H, J=1.8 and 8.1 Hz), 6.73 (t, 2H, J=8.1Hz), 5.97 (s, 2H), 5.92 (s, 2H); ¹⁹F NMR (CDCl₃): - 47591; LCMS: ret.time: 21.74 min.; purity: 97%; MS (m/e): 369 (MH⁺). 7.3.84N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-fluoro-2,4-pyrimidinediamine(R925791) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and tyramine were reacted to yieldN2,N4-bis[2-(4-hydroxyphenyl)ethyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ9.17 (bs, 1H), 8.22 (bs, 1H), 6.99 (d, 4H, J=8.1 Hz),6.65 (d, 4H, J=8.1 Hz), 3.48-3.43 (m, 4H), 2.72 (t, 4H, J=7.7 Hz); LCMS:ret. time: 19.19 min.; purity: 100 %; MS (m/e): 369 (MH⁺). 7.3.85N2,N4-Bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine (R945057) Inlike manner to the preparation ofN2,N-4-bis(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine,4-aminobenzonitrile and 2,4-dichloro-5-fluoropyrimidine gaveN2,N4-bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ7.26 (d, J=8.7 Hz, 2 H), 7.36 (d, J=9.0 Hz, 2 H), 7.43 (d,J=8.7 Hz, 2 H), 7.60 (d, J=8.7 Hz, 2 H), 7.86 (d, J=3.6 Hz, 1 H), 9.49(br, 1 H, NH), 9.51 (br, 1 H, NH); ¹⁹F NMR (282 MHz, DMSO-d₆): δ-161.48; LC: 27.15 min.; 100%; MS (m/e): 331.00 (MH⁺). 7.3.86N2,N4-Bis(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R926234) In amanner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-ethylaniline were reacted to yieldN2,N4-bis(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (CDCl₃):δ8.83 (bs, 1H), 7.77 (d, 1H. J=3.9 Hz), 7.48 (d, 2H, J=8.7 Hz), 7.40 (d,2H, J=8.7 Hz), 7.31 (bs, 1H), 7.18 (d, 2H, J=8.7 Hz), 7.11 (d, 2H, J=8.7Hz), 2.68-2.61 (m, 4H), 1.28-1.21 (m, 6H); LCMS: ret. time: 29.17 min.;purity: 100 %; MS (m/e): 337(MH⁺). 7.3.87N2,N4-Bis(3-chloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926675) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-hydroxyaniline werereacted to yieldN2,N4-bis(3-chloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ7.83 (d, 1H, J=4.2 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.53 (d,1H, J=2.4 Hz), 7.40 (dd, 1H, J=2.4 and 8.7 Hz), 7.20 (dd, 1H, J=2.4 and8.7 Hz), 6.89 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=8.7 Hz); ¹⁹F NMR(CD₃OD): - 47862; LCMS: ret. time: 17.89 min.; purity: 99 %; MS (m/e):382 (MH⁺). 7.3.88N2,N4-Bis[3-chloro-4-(ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R926676) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and3-chloro-4-(ethoxycarbonylmethyleneoxy)aniline were reacted to yieldN2,N4-bis[3-chloro-4-(ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.93 (bs, 1H), 7.67-7.65 (m, 2H), 7.41 (dd, 1H, J=3.0and 9.3 Hz), 7.26 (dd, 1H, J=2.7 and 9.3 Hz), 6.92-6.85 (m, 3H), 6.69(d, 1H, J=2.4 Hz), 4.71 (s, 2H), 4.66 (s, 2H), 4.32-4.23 (m, 4H),1.33-1.27 (m, 6H); ¹⁹F NMR (CDCl₃): - 47274; LCMS: ret. time: 27.51min.; purity: 97 %; MS (m/e): 553 (M⁺). 7.3.89N2,N4-Bis(3-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926681) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-fluoro-4-hydroxyaniline werereacted to yieldN2,N4-bis(3-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ7.83 (d, 1H), 7.53 (dd, 1H), 7.42 (dd, 1H), 7.22 (dq, 1H),7.03 (dq, 1H), 6.89 (d, 1H), 6.83 (s, 1H), 6.80 (s, 1H), 6.78 (d, 1H);¹⁹F NMR (CDCl₃): - 390060, - 39165, - 47835; LCMS: ret. time: 15.27min.; purity: 95 %; MS (m/e): 349 (MH⁺). 7.3.90N2,N4-Bis(3-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine (R926682) Ina manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-aminoacetanilide were reacted toyield N2,N4-bis(3-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ10.24 (bs, 1H), 10.03 (s, 1H), 9.94 (s, 1H), 8.20 (d,1H, J=4.8 Hz), 7.91 (bs, 1H), 7.68 (bs, 1H), 7.43 (d, 1H, J=8.1 Hz),7.35-7.30 (m, 2H), 7.24-7.19 (m, 2H), 7.11 (t, 1H, J=8.1 Hz), 2.03 (s,3H), 2.01 (s, 3H); LCMS: ret. time: 15.10 min.; purity: 99 %; MS (m/e):395 (MH⁺). 7.3.91N2,N4-Bis(2-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926683) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-fluoro-4-hydroxyaniline werereacted to yieldN2,N4-bis(2-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ9.78 (s, 1H), 9.50 (s, 1H), 8.75 (s, 1H), 8.06 (s, 1H),7.87 (d, 1H, J=4.2 Hz), 7.25-7.18 (m, 2H), 6.61 (dd, 1H, J=2.4 and 12.3Hz), 6.56-6.47 (m, 2H), 6.39 (dd, 1H, J=1.8 and 8.7 Hz); LCMS: ret.time: 15.52 min.; purity: 99 %; MS (m/e): 349 (MH⁺). 7.3.92N2,N4-Bis(4-isopropoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926701)In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-isopropoxyaniline were reacted toyield N2,N4-bis(4-isopropoxy)phenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ7.89 (bs, 1H), 7.47 (d, 2H, J=8.7 Hz), 7.38 (d, 2H, J=9.0Hz), 6.87 (d, 2H, J=9.0 Hz), 6.83 (d, 2H, J=8.7 Hz); LCMS: ret. time:27.51 min.; purity: 98 %; MS (m/e): 397 (MH⁺). 7.3.93N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine(R925771) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 3,4-ethylenedioxyaniline were reactedto yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ8.07 (bs, 1H), 7.16 (d, 1H, J=3.0 Hz), 7.10 (d, 1H, J=2.7 Hz),6.98-6.93 (m, 2H), 6.90-6.75 (m, 3H), 4.28-4.21 (m, 8H); LCMS: ret.time: 22.61 min.; purity: 100%; MS (m/e): 458 (MH⁺). 7.3.94N2,N4-Bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine (R925778) In amanner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 3-aminophenol were reacted to yieldN2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ9.99 (bs, 1H), 9.34 (bs, 1H), 8.30 (s, 1H), 7.15 (t, 1H,J=8.4 Hz), 7.06-6.97 (m, 2H), 6.94-6.92 (m, 2H), 6.80 (bs, 1H), 6.62 (s,1H, J=8.1 Hz), 6.43 (d, 1H, J=7.8 Hz); LCMS: ret. time: 18.48 min.;purity: 97%; MS (m/e): 374 (MH⁺). 7.3.95N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-bromo-2,4-pyrimidinediamine(R925779) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and ethyl 4-aminophenoxyacetate werereacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-bromo-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.12 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 7.42 (d,4H, J=8.7 Hz), 6.89 (d, 2H, J=9.0 Hz), 6.71 (d, 2H, J=9.3 Hz), 4.78 (s,2H), 4.66 (s. 2H), 4.20-4.10 (m, 4H), 1.23-1.16 (m, 6H); LCMS: ret.time: 25.82 min.; purity: 94%; MS (m/e): 546 (MH⁺). 7.3.96N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-bromo-2,4-pyrimidinediamine(R925792) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and tyramine were reacted to yieldN2,N4-bis[2-(4-hydroxyphenyl)ethyl]-5-bromo-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ7.83 (s, 1H), 6.96 (d, 4H, J=8.1 Hz), 6.63 (d, 4H, J=8.1Hz), 3.54-3.42 (m, 2H), 2.74-2.66 (m, 2H), 2.74-2.66 (m, 4H); ret. time:20.10 min.; purity: 100 %; MS (m/e): 430 (MH⁺). 7.3.97N2,N4-Bis(2-phenylphenyl)-5-bromo-2,4-pyrimidinediamine (R925798) In amanner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 2-aminobiphenyl were reacted to yieldN2,N4-bis(2-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. ¹H NMR (CDCl₃):δ8.34 (d, 1H, J=8.1 Hz), 8.27 (d, 1H, J=8.1 Hz), 8.00 (s, 1H), 7.51-7.18(m, 17H), 6.95 (s, 1H); LCMS: ret. time: 18.87 min.; purity: 97 %; MS(m/e): 495 (MH⁺). 7.3.98N2,N4-Bis(2-methoxy-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine(R925799) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 5-phenyl-ortho-anisidine were reactedto yieldN2,N4-bis(2-methoxy-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ8.26 (m, 2H), 8.05 (m, 2H), 7.39-7.21 (m, 12H), 7.17(dd, 1H, J=2.4 and 8.1 Hz), 7.11 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=9.0Hz), 3.88 (s, 3H), 3.83 (s, 3H); LCMS: ret. time: 20.51 min.; purity: 98%; MS (m/e): 554 (MH⁺). 7.3.99N2,N4-Bis(4-methoxy-3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine(R925802) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, with theaddition of triethylamine, 5-bromo-2,4-dichloropyrimidine and3-phenyl-para-anisidine hydrochloride were reacted to yieldN2,N4-bis(4-methoxy-3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ8.26 (m, 2H), 8.06 (m, 2H), 7.38-7.25 (m, 12H), 7.18(dd, 1H, J=2.4 and 8.1 Hz), 7.12 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, 8.7Hz), 3.89 (s, 3H), 3.83 (s, 3H); LCMS: ret. time: 36.77 min.; purity: 98%; MS (m/e): 554 (MH⁺). 7.3.100N2,N4-Bis(3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine (R925803) In amanner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-bromo-2,4-dichloropyrimidine and 3-aminobiphenyl were reacted to yieldN2,N4-bis(3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ9.86 (bs, 1H), 9.20 (bs 1H), 8.33 (s, 1H), 7.79 (bs, 1H),7.18 (bs, 1H), 7.61 (d, 1H), 7.56-7.51 (m, 2H), 7.48-7.23 (m, 11H),7.17-7.04 (m, 2H); LCMS: ret. time: 19.52 min.; purity: 80 %; MS (m/e):494 (MH⁺). 7.3.101N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-cyano-2,4-pyrimidinediamine(R925773) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and 3,4-ethylenedioxyaniline were reactedto yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-cyano-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ9.69 (bs, 1H), 9.28 (bs, 1H), 8.40 (s, 1H), 7.16-6.89 (m,4H), 6.79 (d, 1H, J=9.0 Hz), 6.65 (bs, 1H), 4.22 (s, 4H), 4.16 (s, 4H);LCMS: ret. time: 24.42 min.; purity: 93 %; MS (m/e): 404 (MH⁺). 7.3.102N2,N4-Bis(3-hydroxyphenyl)-5-cyano-2,4-pyrimidinediamine (R925774) In amanner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and 3-hydroxyaniline were reacted toyield N2,N4-bis(3-hydroxyphenyl-5-cyano-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ9.73 (bs, 1H), 9.40 (s, 1H), 9.33 (bs, 1H), 9.24 (s, 1H),8.47 (s, 1H), 7.20 (d, 1H, J=7.5 Hz), 7.11 (t, 1H, J=7.5 Hz), 7.09-7.02(m, 2H), 6.99-6.89 (m, 3H), 6.54 (d, 1H, J=7.2 Hz), 6.37 (dd, 1H, J=1.8and 8.4 Hz); LCMS: ret. time: 19.71 min.; purity: 97%; MS (m/e): 320(MH⁺). 7.3.103N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-cyano-2,4-pyrimidinediamine(R925775) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and ethyl 4-aminophenoxyacetatewerereacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.80 (s, 1H), 7.40 (d, 4H, J=8.7 Hz), 6.90 (4H, J=9.0Hz), 6.82-6.75 (m, 2H). 4.60 (bs, 4H), 4.29-4.25 (m, 4H), 1.32-1.26 (m,5H), LCMS: ret. time: 28.50 min.; purity: 100 %; MS (m/e): 493 (MH⁺).7.3.104 R935192: N2,N4-Bis(1-methyl-indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine: In likemanner to the preparation of N2, N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoropyrimidine and 1-methyl-5-aminoindazole were reacted toproduce N2,N4-bis(1-methyl-indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ10.65 (s, 1H), 10.41 (s, 1H), 8.29 (d, 1H, J=5.3 Hz), 7.98(s, 1H), 7.79 (d, 2H, J=9.4 Hz), 7.69-7.54 (m, 4H), 7.35 (dd, 1H, J=1.7and 9.4 Hz), 4.03 (s, 3H), 4.01 (s, 3H). LCMS: ret. time: 16.86 min.;purity: 99%; MS (m/e): 389 (MH⁺). 7.3.105 R935205: N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamineIn like manner to the preparation of 5-fluoro-N2, N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrmidineand 6-amino-1-(methoxycarbonyl)methyl-indazoline were reacted to produceN2,N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.59 (s, 1H), 9.45 (s, 1H), 8.18 (d, 1H, J=3.5 Hz),8.11 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.69 (d, 1H,J=8.8 Hz), 7.58 (d, 1H, J=8.8 Hz), 7.48 (dd, 1H, J=1.7 and 8.8 Hz), 7.32(d, 1H, J=8.8 Hz), 5.17 (s, 2H), 4.88 (s, 1H), 3.58 (s, 3H), 3.58 (s,3H). LCMS: ret. time: 17.80 min.; purity: 99%; MS (m/e): 505 (MH⁺).7.3.106 R935211: N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrmidine and6-amino-1-(methoxycarbonyl)methyl-indazoline was reacted to produce N2,N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.37 (s, 1H), 9.17 (s, 1H), 8.11-8.06 (m, 3H), 7.94(s, 1H), 7.70 (s, 1H), 7.63 (s, 2H), 7.46 (s, 2H), 5.40 (s, 2H), 5.31(s, 2H), 3.67 (s, 3H), 3.64 (s, 3H). LCMS: ret. time: 17.06 min.;purity: 96%; MS (m/e): 505 (MH⁺). 7.3.107 R935188:N2,N4-Bis(indazolin-6-yl)-5-fluoro-2,4-pyrimidinediamine: In like mannerto the preparation of 5-fluoro-N2, N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2,4-dichlro-5-fluoropyrimidineand 6-aminoindazoline were reacted to produceN2,N4-bis(indazolin-6-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ9.80 (s, 1H), 9.65 (s, 1H), 8.20 (d, 1H, J=4.1 Hz), 8.01 (s,1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.69 (d, 1H, J=8.8 Hz),7.57 (d, 1H, J=8.3 Hz), 7.54 (dd, 1H, J=1.7 and 8.8 Hz), 7.29 (dd, 1H,J=1.7 and 8.8 Hz); LCMS: ret. time:15.17 min.; purity: 94%; MS (m/e):361 (MH⁺). 7.3.108 R935189: N2,N4-Bis(indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine: In like manner tothe preparation of N2, N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-aminoindazole were reacted toproduce N2, N4-bis(indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ10.05 (s, 1H), 9.76 (s, 1H), 8.16 (d, 1H, J=4.7 Hz),8.05 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.52-7.52 (m,2H), 7.44 (d, 1H, J=8.8 Hz), 7.34 (dd, 1H, J=1.7 and 8.8 Hz); LCMS: ret.time: 14.33 min.; purity: 100%; MS (m/e): 361 (MH⁺). 7.3.109N2,N4-Bis(1-ethoxycarbonyl-2-methylpropyl)-5-cyano-2,4-pyrimidinediamine(R925814) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and valine ethyl ester were reacted toyieldN2,N4-bis(1-ethoxycarbonyl-2-methylpropyl)-5-cyano-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.15 (s, 1H), 6.10 (d, 1H, J=8.4 Hz), 5.67 (d, 1H,J=8.1 Hz), 4.66-4.62 (m, 1H), 4.50-4.46 (m, 1H), 4.25-4.13 (m, 4H),2.27-2.14 (m, 2H), 1.31-1.24 (m, 6H), 1.00-0.94 (m, 12H); LCMS: ret.time: 30.41 min.; purity: 98 %; MS (m/e): 392 (MH⁺). 7.3.110N2,N4-Bis(1-methoxycarbonyl-3-methylbutyl)-5-cyano-2,4-pyrimidinediamine(R925815) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and leucine methyl ester were reacted toyieldN2,N4-bis(1-methoxycarbonyl-3-methylbutyl)-5-cyano-2,4-pyrimidinediamine.¹H NMR (CDCl₃): mixture of rotamers δ8.15 (s, 1H), 6.10 and 5.49 (2d,1H, J=8.1 Hz), 5.53 (d, 1H, J=8.4 Hz), 4.80-4.67 (m, 1H), 4.57-4.48 (m,1H), 3.73 (s, 3H), 3.71 (s, 3H), 1.78-1.60 (m, 6H), 0.97-0.89 (m, 12H);LCMS: ret. time: 30.33 min.; purity: 91 %; MS (m/e): 392 (MH⁺). 7.3.111N2,N4-Bis(methoxycarbonylbenzyl)-5-cyano-2,4-pyrimidinediamine (R925819)In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and phenyl glycine methyl ester werereacted to yieldN2,N4-bis(methoxycarbonylbenzyl)-5-cyano-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): mixture of rotamers δ8.15 (s, 1H), 7.69-7.60 (m, 1H), 7.42-7.32(m, 10H), 6.20 and 5.73 (2d, 1H, J=6.6 Hz), 6.14 and 5.65 (2d, 1H, J=6.3Hz), 5.55 (d, 1H, J=6.3 Hz), 5.39 (t, 1H, J=7.2 Hz), 3.79 and 3.78 (2s,3H), 3.67 and 3.65 (2s, 3H); LCMS: ret. time: 30.22 min.; purity: 91 %;MS (m/e): 432 (MH⁺). 7.3.112N2,N4-Bis[4-(ethoxycarbonylmethyl)phenyl]-5-cyano-2,4-pyrimidinediamine(R926662) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-cyanopyrimidine and ethyl 4-aminophenylacetate werereacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyl)phenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.29 (bs, 1H), 7.46 (2d, 4H, J=7.8 Hz), 7.28 (d, 2h,J=8.1 Hz), 7.19 (d, 2H, J=8.1 Hz), 4.16 (2q, 4H, J=6.3 Hz), 3.64 (s,2H), 3.59 (s, 2H), 1.30-1.23 (m, 6H); LCMS: ret. time: 29.29 min.;purity: 93%; MS (m/e): 461 (MH⁺). 7.3.113 R935000:N2,N4-Bis(2-methoxy-5-phenylphenyl)-5-methyl-2,4-pyrimidinediamine Inlike manner to the preparation of5-fluoro-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine,5-phenyl-2-anisidine and 2,4-dichloro-5-methylpyrimidine were reacted toprovideN2,N4-bis(2-methoxy-5-phenylphenyl)-5-methyl-2,4-pyrimidinediamine. ¹HNMR (CDCl₃ + CD₃OD): δ7.76 (d, 1H, J=2.3 Hz), 7.57 (s, 1H), 7.56 (s,1H), 7.02-6.85 (m, 8H), 6.86-6.80 (m, 4H), 6.72 (d, 2H), 3.73 (s, 3H),3.72 (s, 3H), 2.07 (s, 3H); LCMS: ret. time: 31.53 min.; purity: 97%; MS(m/e): 489 (MH⁺). 7.3.114 R935001:N2,N4-Bis[(2-methyl-5-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-phenyl-2-toluidine and 2,4-dichloro-5-methylpyrimidine were reacted toproduceN2,N4-bis[(2-methyl-5-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ7.59-7.55 (m, 1H), 7.45 (d, 2H, J=3.6 Hz), 7.26-7.17 (m,6H), 7.09-6.98 (m, 8H), 2.36 (s, 3H), 2.22 (s, 3H), 2.21(s, 3H); LCMS:ret. time: 32.44 min.; purity: 90%; MS (m/e): 457 (MH⁺). 7.3.115R935002:N2,N4-Bis[(4-methoxy-3-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,3-phenyl-4-anisidine hydrochloride and 2,4-dichloro-5-methylpyrimidinewith an added diisopropylethylamine were reacted to produceN2,N4-bis[(4-methoxy-3-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ8.15 (d, 1H, J=2.3 Hz), 7.76 (t, 1H, J=2.3 Hz), 7.71 (s, 1H), 7.59 (s, 1H), 7.16 -7.03 (m, 8H), 6.98-6.81 (5H), 3.96 (s, 3H), 3.89(s, 3H), 2.21 (s, 3H); LCMS: ret. time: 32.01 min.; purity: 90%; MS(m/e): 489 (MH⁺). 7.3.116 R935003:N2,N4-Bis[(4-phenyl-2-methoxy-5-methyl)phenyl]-5-methyl-2,4-pyrimidinediamineIn like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,5-methyl-4-phenyl-2-anisidine and 2,4-dichloro-5-methylpyrimidine werereacted to produceN2,N4-bis[(4-phenyl-2-methoxy-5-methyl)phenyl]-5-methyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ9.25 (br s, 1H), 8.17 (s, 1H), 7.77 (t, 1H, J=6.4 Hz),7.66 (s, 2H), 7.43-7.25 (m, 10H), 6.79 (s, 2H), 3.91 (s, 3H), 3.85 (s,3H), 2.20 (s, 3H), 2.09 (s, 3H), 2.02 (s, 3H); LCMS: ret. time: 31.10min.; purity: 100%; MS (m/e): 517 (MH⁺). 7.3.117 R935004:N2,N4-Bis[[di-(4-methoxyphenyl)]methyl]-5-fluoro-2,4-pyrimidinediamineIn like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,1,1-di(4-anisyl)methylamine and 2,4-dichloro-5-fluoropyrimidine werereacted to produceN2,N4-bis[[di-(4-methoxyphenyl)]methyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃ + CD₃OD): δ7.91 (d, 1H, J=2.3 Hz), 7.18 (d, 8H, J=9.0 Hz),6.85 (d, 8H, J=9.0 Hz), 6.40 (d, 1H, J=8.2 Hz), 5.39 (d, 1H, J=7.1 Hz),3.81 (s, 6H), 3.78 (s, 6H); LCMS: ret. time: 32.76 min.; purity: 95%; MS(m/e): 581 (MH⁺). 7.3.118 R935005:N2,N4-Bis(diphenylmethyl)-5-fluoro-2,4-pyrimidinediamine In like mannerto the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 1,1-diphenylmethylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produceN2, N4-bis(diphenylmethyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(CDCl₃): δ7.91 (d, 1H, J=2.3 Hz), 7.39-7.25 (m, 20H), 6.51 (d, 1H, J=8.2Hz), 5.77 (d, 1H, J=7.0 Hz); LCMS: ret. time: 33.46 min.; purity: 92%;MS (m/e): 461 (MH⁺). 7.3.119 R935006:N2,N4-Bis[di-(4-chlorophenyl)methyl]-5-fluoro-2,4-pyrimidinediamine Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,benzhydrylamine and 2,4-dichloro-5-fluoropyrimidine were reacted toyieldN2,N4-bis[di-(4-chlorophenyl)methyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃ + CD₃OD): δ7.94 (d, 1H, J=2.3 Hz), 7.40-7.20 (m, 16H), 6.46(d, 1H, J=8.2 Hz), 5.69 (d, 1H, J=7.0 Hz); LCMS: ret. time: 32.83 min.;purity: 90%; MS (m/e): 599 (MH⁺). 7.3.120 R935016:N2,N4-Bis[1(R)-4-methoxyphenylethyl]-5-bromo-2,4-pyrimidineamine In likemanner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,(R)-(+)-1-(4-methoxyphenyl)ethylamine and 5-bromo-2,4-dichloropyrimidinewere reacted to produceN2,N4-bis[1(R)-4-methoxyphenylethyl]-5-bromo-2,4-pyrimidineamine. ¹H NMR(CDCl₃): δ7.81 (s, 1H), 7.25 (d, 4H, J=8.4 Hz), 6.86 (app t, 4H, J=8.4and 8.7 Hz), 5.27-5.20 m (2H), 5.09 (dq, 1H, J=6.4 and 7.0 Hz), 4.89(dq, 1H, J=6.4 and 7.0 Hz), 3.80 (s, 3H), 3.79 (s, 3H), 1.40 (d, 6H,J=7.0 Hz). 7.3.121 R935075: N2,N4-Bis[3-(2-hydroxyethoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine In likemanner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-(3-aminophenoxy)ethanol werereacted to produceN2,N4-bis[3-(2-hydroxyethoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ9.50 (br s, 1H), 9.35 (br s, 1H), 8.13 (d, 1H, J=4.1Hz), 7.44 (d, 1H, J=7.6 Hz), 7.26-7.19 (m, 4H), 7.10 (t, 1H, J=7.6 Hz),6.65 (dd, 1H, J=2.3 and 8.2 Hz), 6.50 (dd, 1H, J=2.3 and 8.2 Hz), 5.0(br s, 2H), 3.91 (t, 2H, J=5.2 Hz), 3.85 (t, 2H, J=5.2 Hz), 3.68 (qt,2H, J=5.2 Hz), 3.66 (qt, 2H, J=5.2 Hz); LCMS: ret. time: 15.76 min.;purity: 97%; MS (m/e): 401 (MH⁺). 7.3.122 R935076:N2,N4-Bis[3-(2-methoxyethyl)oxyphenyl]-5-fluoro-2,4-pyrimidinediamine:In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-(2-methoxyethoxy)aniline werereacted to produceN2,N4-bis[3-(2-methoxyethyl)oxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.96 (d, 1H, J=2.9 Hz), 7.36 (t, 1H, J=1.7 Hz), 7.28(t, 1H J=1.7 Hz), 7.25-7.06 (m, 4H), 6.98 (br s, 1H), 6.75 (d, 1H, J=2.3Hz), 6.70 (dd, 1H, J=1.7 and 8.2 Hz), 6.58 (dd, 1H, J=1.7 and 8.2 Hz),4.08-4.03 (m, 4H), 3.74-3.69 (m, 4H), 3.44 (s, 3H), 3.43 (s, 3H); LCMS:ret. time: 21.01 min.; purity: 97%; MS (m/e): 429 (MH⁺). 7.3.123R935077:N2,N4-Bis(5-hydroxy-2-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,3-amino-4-isopropylphenol and 2,4-dichloro-5-fluoropyrimidine werereacted to produceN2,N4-bis(5-hydroxy-2-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.93 (d, 1H, J=3.5 Hz), 7.79 (br s, 1H), 7.64 (br s,1H), 7.13 (d, 1H, J=8.7 Hz), 7.06 (d, 1H, J=2.3 Hz), 7.05 (d, 1H, J=8.7Hz), 6.89 (d, 1H, J=2.3 Hz), 6.66 (d, 1H, J=2.3 and 8.7 Hz), 6.57 (d,1H, J=2.3 and 8.7 Hz), 2.96 (m, 2H), 1.25 (d, 6H, J=7.0 Hz), 1.13 (dd,6H, J=7.0 Hz); LCMS: ret. time: 24.27 min.; purity: 97%; MS (m/e): 397(MH⁺). 7.3.124 R935114:N2,N4-Bis(3-methoxycarbonylmethylenephenyl)-5-fluoro-2,4-pyrimidinediamineIn like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-(methoxycarbonylmethylene)anilinewere reacted to produce the desiredN2,N4-bis(3-methoxycarbonylmethylenephenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.23 (br s, 1H), 10.05 (br s, 1H), 8.26 (d, 1H,J=4.6 Hz), 7.64 (d, 1H, J=8.2 Hz), 7.51 (br s, 1H), 7.46 (d, 1H, J=8.2Hz), 7.33 (br s, 1H), 7.29 (t, 1H, J=7.6 Hz), 7.20 (t, 1H, J=7.6 Hz),7.06 (d, 1H, J=7.6 Hz), 6.93 (d, 1H, J=7.6 Hz), 3.63 (s, 2H), 3.58 (s,3H), 3.57 (s, 3H), 3.56 (s, 2H); LCMS: ret. time: 21.74 min.; purity:92%; MS (m/e): 425 (MH⁺). 7.3.125 R935162: N2,N4-Bis(3,4-propylenedioxyphenyl)- 5-fluoro-2,4-pyrimidinediamine: Inlike manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and (3,4-propylenedioxy)aniline werereacted to giveN2,N4-bis(3,4-propylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ9.18 (s, 1H), 9.07 (s, 1H), 8.03 (d, 1H, J=3.5 Hz), 7.38(dd, 1H, J=2.3 and 8.2 Hz), 7.35 (d, 1H, J=2.3 Hz), 7.33 (d, 1H, J=2.3Hz), 7.18 (dd, 1H, J=2.3 and 8.8 Hz), 6.90 (d, 1H, J=8.8 Hz), 6.80 (d,1H, J=8.2 Hz), 4.11-3.98 (m, 8H), 2.09-2.01 (m, 4H); LCMS: ret. time:21.40 min.; purity: 97%; MS (m/e): 425 (MH⁺). 7.3.126 R935163:N2,N4-Bis(3-chloro-4-fluoropheny)-2,4-pyrimidinediamine: In like mannerto the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline werereacted to produce N2,N4-bis(3-chloro-4-fluoropheny)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ9.58 (s, 1H), 9.48 (s, 1H), 8.17 (d, 1H, J=4.1 Hz), 7.94-7.90 (m, 2H),7.73-7.67 (m, 1H), 7.51-7.45 (m, 1H), 7.38 (t, 1H, J=8.8 Hz), 7.26 (t,1H, J=8.8 Hz); LCMS: ret. time: 27.83 min.; purity: 99%; MS (m/e): 386(MH⁺). 7.3.127N2,N4-Bis(3-hydroxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R925849) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and 3-aminophenol werereacted to yieldN2,N4-bis(3-hydroxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.56 (bs, 1H), 10.32 (bs, 1H), 9.54 (s, 1H), 9.32(bs, 1H), 7.22-7.15 (m, 2H), 7.02-6.96 (m, 1H), 6.93-6.82 (m, 2H),6.81-6.74 (m, 1H), 6.67 (d, 1H, J=9.3 Hz), 6.43 (d, 1H, J=8.1 Hz), 4.35(q, 2H, J=6.9 Hz), 1.30 (t, 3H, J=6.9 Hz); LCMS: ret. time: 26.01 min.;purity: 96 %; MS (m/e): 412 (MH⁺). 7.3.128N2,N4-Bis(3,4-ethylendioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R925852) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and3,4-ethylenedioxyaniline were reacted to yieldN2,N4-bis(3,4-ethylendioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.52 (s, 1H), 10.28 (s, 1H), 7.07-7.01 (m, 2H), 6.96(dd, 1H, J=1.8 and 8.7 Hz), 6.90-6.84 (m, 2H), 6.61 (d, 1H, J=8.7 Hz),4.33 (q, 2H, J=6.9 Hz), 4.24 (s, 4H), 4.17 (s, 4H), 1.29 (t, 3H, J=6.9Hz); LCMS: ret. time: 30.40 min.; purity: 100 %; MS (m/e): 496 (MH⁺).7.3.129N2,N4-Bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R925864) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, with theaddition of triethylamine,2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and glycine ethyl esterhydrochloride were reacted to yieldN2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): mixture of rotamers δ8.99 and 8.80 (2bs, 1H), 6.22 and6.00 (2bs, 1H), 4.45 (t, 2H, J=7.2 Hz), 4.31-4.21 (m, 6H), 4.14 (d, 2H,J=5.1 Hz), 1.39 (t, 3H, J=7.2 Hz), 1.34-1.28 (m, 6H); LCMS: ret. time:26.06 min.; purity: 99 %; MS (m/e): 400 (MH⁺). 7.3.130N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-2,4-pyrimidinediamine (R925790) In amanner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and tyramine were reacted to yieldN2,N4-bis[2-(4-hydroxyphenyl)ethyl]-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ11.56 (bs, 1H), 9.23 (s, 1H), 8.89 (bs, 1H), 7.92 (bs, 1H),7.60 (d, 1H, J=6.9 Hz), 6.99 (d, 4H, J=8.1 Hz), 6.65 (d, 4H, J=8.1 Hz),6.00 (d, 1H, J=7.2 Hz), 3.59-3.42 (m, 4H), 2.76-2.67 (m, 4H); LCMS: ret.time: 17.93 min.; purity: 95 %; MS (m/e): 351 (MH⁺). 7.3.131N2,N4-Bis(2-phenylphenyl)-2,4-pyrimidinediamine (R925804) In a mannersimilar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 2-aminobiphenyl were reacted to yieldN2,N4-bis(2-phenylphenyl)-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ8.36(d, 1H, J=8.1 Hz), 7.97 (d, 1H, J=5.7 Hz), 7.80 (d, 1H, J=7.5 Hz),7.50-7.21 (m, 15H), 7.12-7.05 (m, 1H), 6.91 (bs, 1H), 6.38 (bs, 1H),6.07 (d, 1H, J=6.0 Hz); LCMS: ret. time: 29.94 min.; purity: 100 %; MS(m/e): 415 (MH⁺). 7.3.132N2,N4-Bis(2-methoxy-5-phenylphenyl)-2,4-pyrimidinediamine (R925805) In amanner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 5-phenyl-ortho-anisidine were reacted toyield N2,N4-bis(2-methoxy-5-phenylphenyl)-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ7.88-7.84 (m, 2H), 7.82 (d, 1H, J=6.9 Hz), 7.30-7.14 (m, 14H),7.10 (dd, 2H, J=3.0 and 8.1 Hz), 6.48 (d, 1H, J=6.9 Hz), 3.93 (s, 3H),3.92 (s, 3H); LCMS: ret. time: 30.09 min.; purity: 94 %; MS (m/e): 476(MH⁺). 7.3.133N2,N4-Bis(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945041) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, from5-amino-2-hydroxybenzoic acid (458 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (235mg, 98%). ¹H NMR (DMSO-d₆): δ6.76 (d, J=9.0 Hz, 1 H), 6.88 (d, J=9.6 Hz,1 H), 7.75 (dd, J=3.0, 9.0 Hz, 1 H), 7.90-7.94 (m, 3 H), 8.02 (d, J=3.9Hz, 1 H), 9.04 (s, 1 H, NH), 9.28 (s, 1 H, NH); ¹⁹F NMR (282 MHz,DMSO-d₆): δ-165.79; LC: 16.02 min, 86.82%; MS (m/z): 400.94 (MH⁺).7.3.134 N2,N4-Bis(4-methoxy-3-phenylphenyl)-2,4-pyrimidinediamine(R925806) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, with theaddition of triethylamine, 2,4-dichloropyrimidine and3-phenyl-para-anisidine hydrochloride were reacted to yieldN2,N4-bis(4-methoxy-3-phenylphenyl)-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ7.93 (d, 1H, J=2.4 Hz), 7.88 (d, 1H, J=2.4 Hz), 7.29 (dd, 1H,J=1.8 and 9.0 Hz), 7.26-7.18 (m, 13H), 7.10 (d, 2H, J=8.7 Hz), 6.46 (d,1H, J=7.2 Hz), 3.93 (s, 3H), 3.92 (s, 3H); LCMS: ret. time: 29.99 min.;purity: 92%; MS (m/e): 476 (MH⁺). 7.3.135N2,N4-Bis(2-methyl-5-phenylphenyl)-2,4-pyrimidinediamine (R925807) In amanner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 5-phenyl-ortho-toluidine were reacted toyield N2,N4-bis(2-methyl-5-phenylphenyl)-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ10.45 (bs, 1H), 10.01 (bs, 1H), 7.86 (bs, 1H), 7.69-7.22 (m,17H), 2.28 (s, 6H); LCMS: ret. time: 18.69 min.; purity: 98 %; MS (m/e):443 (MH⁺). 7.3.136N2,N4-Bis(2-methoxy-5-methyl-4-phenylphenyl)-2,4-pyrimidinediamine(R925808) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 5-methyl-4-phenyl-ortho-anisidine werereacted to yieldN2,N4-bis(2-methoxy-5-methyl-4-phenylphenyl)-2,4-pyrimidinediamine.¹HNMR (DMSO-d₆): δ9.99 (bs, 1H), 9.22 (bs, 1H), 7.98 (d, 1H, J=6.3 Hz),7.75 (s, 1H), 7.59 (s, 1H), 7.46-7.29 (m, 10H), 6.92 (s, 1H), 6.87 (s,1H), 6.49 (d, 1H, J=5.4 Hz), 3.82 (s, 3H), 3.81 (s, 3H), 2.07 (s, 3H),1.98 (s, 3H); LCMS: ret. time: 19.69 min.; purity: 93 %; MS (m/e): 503(MH⁺). 7.3.137N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine(R925862) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-trifluoromethylpyrimidine and ethyl 4-aminophenoxyacetatewere reacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.64 (bs, 1H), 8.80 (bs, 1H), 8.29 (s, 1H), 7.36 (d,2H, J=8.1 Hz), 7.31 (d, 2H, J=9.3 Hz), 6.93 (d, 2H, J=8.7 Hz), 6.70 (d,2H, J=9.0 Hz), 4.80 (s, 2H), 4.67 (s, 2H), 4.18 (q, 2H, J=6.9 Hz), 4.15(q, 2H, J=6.9 Hz), 1.20 (t, 3H, J=6.9 Hz), 1.19 (t, 3H, J=6.9 Hz); ¹⁹FNMR (DMSO-d₆): -16932; LCMS: ret. time: 26.33 min.; purity: 98 %; MS(m/e): 535 (MH⁺). 7.3.138N2,N4-Bis(3-hydroxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine(R925863) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-trifluoromethylpyrimidine and 3-aminophenol were reactedto yieldN2,N4-bis(3-hydroxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ9.82 (bs, 1H), 8.88 (bs, 1H), 8.36 (s, 1H), 7.18-7.11(m, 2H), 6.96 (m, 4H), 6.63 (dd, 1H, J=2.4 and 8.1 Hz), 6.38 (d, 1H,J=8.1 Hz); ¹⁹F NMR (DMSO-d₆): -16979; LCMS: ret. time: 19.04 min.;purity: 95 %; MS (m/e): 363 (MH⁺). 7.3.139N2,N4-Bis[4-(ethoxycarbonylmethyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine(R926663) In a manner similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-trifluoromethylpyrimidine and ethyl 4-aminophenylacetatewere reacted to yieldN2,N4-bis[4-(ethoxycarbonylmethyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.31 (s, 1H), 7.46 (d, 2H, J=9.0 Hz), 7.45 (d, 2H,J=8.7 Hz), 7.30 (d, 2H, J=9.0 Hz), 7.18 (d, 2H, J=8.7 Hz), 7.16 (bs,1H), 6.82 (bs, 1H), 4.16 (2q, 4H, J=7.8 Hz), 3.64 (s, 2H), 3.57 (s, 2H),1.27 (t, 3H, J=7.8 Hz), 1.26 (t, 3H, J=7.8 Hz); ¹⁹F NMR (CDCl₃): -17223;LCMS: ret. time: 28.07 min.; purity: 99 %; MS (m/e): 504 (MH⁺). 7.3.140N2,N4-Bis(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926623) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2,5-dimethyl-4-hydroxyaniline werereacted to yieldN2,N4-bis(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.63 (d, 1H, J=4.2 Hz), 7.05 (s, 1H), 6.97 (s, 1H),6.64 (1H), 6.54 (s, 1H), 2.12 (s, 6H), 2.06 (s, 3H), 2.03 (s, 3H), 2.03(s, 3H); ¹⁹F NMR (CD₃OD): -48488; LCMS: ret. time: 18.28; purity; 94%;MS (m/e): 369 (MH⁺). 7.3.141N2,N4-Bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine (R926461) Thereaction of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith 2 equivalents of sodium methoxide in methanol followed by removalof solvent gave the requisite compound,N2,N4-bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (D₂O):δ7.65 (bd, 1H), 7.00-6.90 (m, 2H), 6.71 (m, 2H), 6.55 (dd, 1H, J=1.2 and6.3 Hz), 6.31 (bd, 1H, J=8.1 Hz), 6.23 (bd, 1H, J=8.7 Hz); ¹⁹F NMR(D₂O): -47016; LCMS: ret. time: 15.68 min.; purity: 99%; MS (m/e): 313(MH⁺). 7.3.142 N2,N4-Bis(3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine(R945051) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,3-aminobenzonitrile (177 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gaveN2,N4-bis(3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine (75 mg, 76%). ¹HNMR (acetone-d ₆): δ7.33 (dt, J=1.8, 7.8 Hz, 1 H), 7.46-7.52 (m, 2 H),7.59 (t, J=7.8 Hz, 1 H), 7.90 (ddd, J=0.9, 2.1 and 8.4 Hz, 1 H), 8.09(ddd, J=1.2, 2.4 and 8.4 Hz, 1 H), 8.17 (d, J=3.3 Hz, 1 H), 8.31 (m, 1H), 8.35 (t, J=2.1 Hz, 1 H), 8.98 (br, 1 H, NH), 9.02 (br, 1 H, NH); ¹⁹FNMR (282 MHz, acetone-d ₆): δ-165.80; LCMS: 24.64 min.; purity: 98.02%;MS (m/e): 331.01 (MH⁺). 7.3.143N2,N4-Bis(benzothiophen-3-ylmethyl)-5-fluoro-2,4-pyrimidinediamine(R945145) Using procedure similar to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,benzothiophen-3-ylmethylamine and 2,4-dichloro-5-fluoropyrimidine gaveN2,N4-bis(benzothiophen-3-ylmethyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ4.82 (dd, J=0.9 and 5.7 Hz, 2 H), 4.86 (dd, J=0.9 and 5.7Hz, 2 H), 5.14 (br, 2 H), 7.31-7.40 (m, 6 H), 7.75-7.89 (m, 5 H); ¹⁹FNMR (282 MHz, CDCl₃): δ-172.12; LCMS: 27.79 min.; purity: 96.47%; MS(m/e): 420.92 (MH⁺). 7.3.144N2,N4-Bis[4-(N-benzylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945152) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 4-(N-benzylpiperazino)aniline (400 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) resultedN2,N4-bis[4-(N-benzylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine(120 mg, 64%). ¹H NMR (CDCl₃): δ2.63 (p, J=2.4 Hz, 8 H), 3.14 (t, J=4.8Hz, 4 H), 3.19 (t, J=4.8 Hz, 4 H), 3.58 (s, 4 H), 6.58 (d, 1 H, NH),6.67 (br, 1 H, NH), 6.87 (d, J=9.3 Hz, 2 H), 6.90 (d, J=9.0 Hz, 2 H),7.33-7.39 (m, 12 H), 7.46 (d, J=9.0 Hz, 2 H), 7.87 (d, J=3.3 Hz, 1 H);¹⁹F NMR (282 MHz, CDCl₃): δ-169.06; LCMS: 16.82 min.; purity: 96.88%; MS(m/e): 629.12 (MH⁺). 7.3.145N2,N4-Bis(3-hydroxy-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945038) In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 3-hydroxy-2-methylaniline (369 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(3-hydroxy-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (180mg, 88%). ¹H NMR (acetone-d ₆): δ2.14 (s, 3 H), 2.22 (s, 3 H), 6.61 (d,J=8.1 Hz, 1 H), 6.78 (t, J=8.7 Hz, 1 H), 6.87 (d, J=7.8 Hz, 1 H), 6.99(d, J=9.0 Hz, 1 H), 7.08 (t, J=7.8 Hz, 1 H), 7.13 (dd, J=3.9, 8.4 Hz, 1H), 8.24 (d, J=5.1 Hz, 1 H), 8.32 (br, 1 H, NH), 8.57 (br, 1 H, NH);LCMS: ret. time: 16.51 min.; purity: 90.47%; MS (m/e): 341.07 (MH⁺).7.3.146 N2,N4-Bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950160) 2,4-Dichloro-5-fluoropyrimidine (4.7 g, 28.1 mmol) wasdissolved in a mixture of MeOH (150 ml) and H₂O (15 ml). 3-nitroaniline(15.5 g, 112 mmol) was added and the mixture was refluxed for 20 hours(100° C. oil-bath temperature). The mixture was cooled to 22° C. andfiltered. The residue was washed carefully with 200 ml MeOH-H₂O (1:1;v/v) and dried under vacuum to give 7.89 g (76%) ofN2,N4-bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine as yellowcrystals. ¹H NMR (DMSO-d₆ + D₂O): δ8.63 (m, 2H), 8.21 (m, 1H), 8.08 (d,1H, J=8.41 Hz), 7.88 (d, 1H, J=8.4 Hz), 7.79 (d, 1H, J=8.4 Hz), 7.70 (d,1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 7.45 (t, 1H, J=8.4 Hz); LCMS:purity: 100%; MS (m/e): 371.30 (M⁺, 100). 7.3.147N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine (R921302)N2,N4-Bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine (4.0 g, 10.8mmol) and Pd/C 10% (1.2 g, 50% water content) were suspended in 300 mlEtOH-10% aqueous HCl (1 : 1) and hydrogenated in a Parr apparatus for 6hours (22° C., 50 psi). The suspension was filtered over celite andcarefully washed with 20 ml DMF-H₂O (1:1; v/v) followed by 50 ml H₂O.The combined filtrates were concentrated under reduced pressure to givepale yellow oil, which was triturated with MeOH to give the product asfine white needles. The precipitate was filtered off and washed withMeOH followed by Et₂O. The remaining crystals were dried under vacuum togive 4.00 g of pure material (100%) as determined by LCMS. The freeamine was obtained by adding 10 ml 1 N NaOH to a solution of 1 gHCl-salt in 5 ml H₂O. The resulting precipitate was filtered, washedwith H₂O and dried under vacuum for 24 hours to giveN2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine (770 mg) as awhite solid. ¹H NMR (CD₃OD): δ7.92 (d, 1H, J=3.6 Hz), 7.31 (t, 1H, J=2.1Hz), 7.21 (t, 1H, J=2.4 Hz), 7.08, (t, 1H, J=8.1 Hz), 6.99 (t, 1H, J=8.1Hz), 6.88 (m, 1H), 6.77 (m, 1H), 6.47 (m, 1H), 6.34 (m, 1H); LCMS:purity: 100%; MS (m/e): 311.07 (M⁺, 100). 7.3.148N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine (R950122) Inlike manner to the preparation ofN2,N4-bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 1,4-diaminobenzene were reacted toprepare N2,N4-bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 11.15 min.; purity: 100%; MS (m/e): 311.09 (MH⁺). 7.3.149N2,N4-Bis[3-(dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950182) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) wasdissolved in a mixture of MeOH (0.3 ml) and H₂O (0.03 ml).N,N-3-dimethyldiaminoaniline (163 mg, 1.2 mmol) was added and themixture was refluxed for 24 hours (70° C. oil-bath temperature). Themixture was cooled to 22° C., concentrated to dryness under reducedpressure and subjected to column chromatography on silica gel(CHCl₃-Acetone, 2 : 1) to giveN2,N4-bis[3-(dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. LCMSpurity: 99.0%; MS (m/e): 367.13 (M⁺, 100). 7.3.150N2,N4-Bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine (R950130)2,4-Dichloropyrimidine (45 mg, 0.30 mmol) was dissolved in a mixture ofMeOH (1 ml) and H₂O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol)was added and the mixture was refluxed for 20 hours (70° C. oil-bathtemperature). The mixture was cooled to 22° C., concentrated to drynessunder reduced pressure and subjected to column chromatography on silicagel (CHCl₃-Acetone, 2:1) to giveN2,N4-bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine. ¹H NMR (CD₃OD):δ8.13 (s, 1H), 6.95 (d, 2H, J=7.5 Hz), 6.82 (d, 2H, J=1.8 Hz), 6.60 (dd,2H, J=1.8, 7.5 Hz), 6.17 (s, 1H), 2.12 (s, 6H); LCMS purity: 97.3%; MS(m/e): 321.09 (M⁺, 100). 7.3.151N2,N4-Bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950129) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) wasdissolved in a mixture of MeOH (1 ml) and H₂O (0.1 ml).3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture wasrefluxed for 20 hours (70° C. oil-bath temperature). The mixture wascooled to 22° C., concentrated to dryness under reduced pressure andsubjected to column chromatography on silica gel (CHCl₃-Acetone, 2:1) togive N2,N4-bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.11 (d, 1H, J=5.1 Hz), 7.98 (bs, 1H) (7.68 (dd, 1H,J=2.4, 8.1 Hz), 7.40-7.55 (m, 4H), 2.43 (s, 3H), 2.42 (s, 3H); LCMS:purity: 95.0%; MS (m/e): 338.66 (M⁺, 70). 7.3.152N2,N4-Bis[(4-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950083) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) wasdissolved in a mixture of MeOH (1 ml) and H₂O (0.1 ml).4-methylsulfonylaminoaniline (335 mg, 1.8 mmol) was added and themixture was refluxed for 24 hours (100° C. oil-bath temperature). Themixture was cooled to 22° C. and filtered. The residue was washedcarefully with MeOH-H₂O (1:1) and dried under vacuum to giveN2,N4-bis[(4-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.86 (s, 1H), 8.65 (s, 1H), 8.53 (bs, 1H), 8.39 (bs,1H), 7.32 (d, 1H, J=3.3 Hz), 7.12 (d, 1H, J=8.7 Hz), 6.98 (d, 1H, J=8.7Hz), 6.62 (d, 1H, J=8.7 Hz), 6.52 (d, 1H, J=8.7 Hz), 2.32 (s, 3H), 2.27(s, 3H); LCMS: purity: 96.8%; MS (m/e): 466.94 (M⁺, 100). 7.3.153N2,N4-Bis(4-benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950090) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) wasdissolved in a mixture of MeOH (1 ml) and H₂O (0.1 ml).4-benzyloxy-3-trifluoromethylaniline (481 mg, 1.8 mmol) was added andthe mixture was refluxed for 2 days (70° C. oil-bath temperature). Themixture was cooled to 22° C., concentrated to dryness under reducedpressure and subjected to column chromatography on silica gel(CHCl₃-Acetone, 9:1) to giveN2,N4-bis(4-benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.51 (s, 1H), 8.05 (s, 1H), 7.38-7.64 (m, 5H),6.94-7.14 (m, 11H), 6.44-6.73 (m, 4H), 4.84 (s, 2H), 4.79 (s, 2H); LCMSpurity: 94.7%; MS (m/e): 628.93 (M⁺, 100). 7.3.154N2,N4-Bis(3-cyano-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950092) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) wasdissolved in a mixture of MeOH (1 ml) and H₂O (0.1 ml).3-cyano-4-hydroxyaniline (241 mg, 1.8 mmol) was added and the mixturewas refluxed for 2 days (70° C. oil-bath temperature). The mixture wascooled to 22° C., concentrated to dryness under reduced pressure andsubjected to column chromatography on silica gel (CHCl₃-Acetone, 9:1) togive N2,N4-bis(4-hydroxy-3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.96 (d, 1H, J=3.5 Hz), 7.82 (d, 1H, J=3.0 Hz), 7.79(d, 1H, J=3.0 Hz), 7.71 (dd, 1H, J=3.0, 8.8 Hz), 7.54 (dd, J=3.0, 8.8Hz), 6.94 (d, 1H, J=8.8 Hz), 6.84 (d, 1H, J=8.8 Hz); LCMS: purity:97.2%; MS (m/e): 362.98 (M⁺, 100). 7.3.155N2,N4-Bis[3-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950100) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) wasdissolved in a mixture of MeOH (1 ml) and H₂O (0.1 ml).3-methylsulfonylaminoaniline (300 mg, 1.5 mmol) was added and themixture was refluxed for 24 hours (70° C. oil-bath temperature). Themixture was cooled to 22° C., concentrated to dryness under reducedpressure and subjected to column chromatography on silica gel(CHCl₃-Acetone, 9:1) to giveN2,N4-bis[3-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆ + CD₃OD): δ8.01 (d, 1H, J=3.5 Hz), 7.46-7.68 (m, 4H),7.49 (t, 1H, J=8.2 Hz), 7.13 (t, 1H, J=8.2 Hz), 6.89 (dd, 1H, J=2.4, 8.2Hz), 6.72 (m, 1H), 2.95 (s, 3H), 2.91 (s, 3H); LCMS: purity: 97.2%; MS(m/e): 466.89 (M⁺, 100). 7.3.156N2,N4-Bis[3-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950108) 2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) wasdissolved in a mixture of MeOH (2 ml) and H₂O (0.2 ml).3-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and themixture was refluxed for 40 hours (70° C. oil-bath temperature). Themixture was cooled to 22° C., concentrated to dryness under reducedpressure and subjected to column chromatography on silica gel(CHCl₃-Acetone, 9:1) to giveN2,N4-bis[3-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆ + CD₃OD): δ7.96 (d, 1H, J=4.1 Hz), 7.83 (m, 1H), 7.60(m, 1H), 7.34-7.42 (m, 2H), 7.15-7.19 (m, 2H), 7.06 (t, 1H, J=8.2 Hz),6.93 (d, 1H, J=8.2 Hz), 1.43 (s, 9H), 1.40 (s, 9H); LCMS: purity: 93.2%;MS (m/e): 511.06 (M⁺, 100). 7.3.157N2,N4-Bis[4-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950120) 2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) wasdissolved in a mixture of MeOH (2 ml) and H₂O (0.2 ml).4-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and themixture was refluxed for 24 hours (70° C. oil-bath temperature). Themixture was cooled to 22° C., concentrated to dryness under reducedpressure and subjected to column chromatography on silica gel(CHCl₃-Acetone, 9:1) to giveN2,N4-bis[4-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆ + CD₃OD): δ7.96 (d, 1H, J=3.5 Hz), 7.63 (d, 2H, J=8.8Hz), 7.49 (d, 2H, J=8.8 Hz), 7.37 (d, 2H, J=8.8 Hz), 7.24 (d, 2H, J=8.8Hz), 1.45 (s, 9H), 1.43 (s, 9H); LCMS: purity: 97.9%; MS (m/e): 511.04(M⁺, 100). 7.3.158N2,N4-Bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950170)N2,N4-Bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(10 mg, 0.02 mmol) was dissolved in EtOH. To this was addedN-methyl-1,2-aminoethane (0.1 ml : 0.1 ml) and the mixture was refluxedfor 3 days (70° C. oil-bath temperature). The mixture was cooled to 22°C., diluted with water and filtered. The residue was subjected to columnchromatography on silica gel (CHCl₃-Acetone, 2:1) to giveN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆ + CD₃OD): δ8.14 (s, 1H), 8.02 (s, 1H), 7.99 (d, 1H,J=2.4 Hz), 7.35-7.68 (m, 5H), 7.17 (s, 1H), 3.41 (m, 2H), 2.75 (m, 2H),2.35 (s, 3H); LCMS: purity: 84.2%; MS (m/e): 561.08 (M⁺, 100). 7.3.159N2,N4-Bis[2-(2-hydroxyethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950167) In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand 2-aminoethanol were reacted to prepareN2,N4-bis[2-(2-hydroxyethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 14.22 min.; purity: 95.7%; MS (m/e): 535.01 (MH⁺).7.3.160N2,N4-Bis[2-(2-aminoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950168) In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand 1,2-diaminoethane were reacted to prepareN2,N4-bis[2-(2-aminoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.15 min.; purity: 95.8%; MS (m/e): 532.99 (MH⁺).7.3.161N2,N4-Bis[2-(2-(N-benzylamino)ethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950169) In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand N-benzyl-1,2-diaminoethane were reacted to prepareN2,N4-bis[2-(2-(N-benzylamino)ethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret.time: 13.15 min.; purity: 95.8%; MS (m/e): 713.10 (MH⁺). 7.3.162N2,N4-Bis[2-(N-morpholinocarbonyl)benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950172) In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand morpholine were reacted toN2,N4-bis[2-(N-morpholinocarbonyl)benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆ + CD₃OD): δ8.13 (d, 1H, J=2.7 Hz), 8.06 (d, 1H, J=2.4Hz), 8.03 (d, 1H, J=3.6 Hz), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.57 (d, 1H,J=9.3 Hz), 7.49 (dd, 1H, J=2.4, 8.4 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.25(s, 1H), 7.05 (s, 1H), 4.09 (m, 4H), 3.65 (m, 4H); LCMS: ret. time:18.04 min.; purity: 83.2%; MS (m/e): 587.04 (MH⁺). 7.3.163N2,N4-Bis[2-(2-N-morpholinoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine(R950173) In like manner to the preparation ofN2,N4-bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[2-(ethoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamineand N-(2-aminoethyleneamino)morpholine were reacted to prepareN2,N4-bis[2-(2-N-morpholinoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆ + CD₃OD): δ8.16 (d, 1H, J=2.4 Hz), 8.03-8.05 (m, 2H),7.71 (dd, 1H, J=1.8, 8.8 Hz), 7.56 (d, 1H, J=8.8Hz), 7.42 (d, 1H, J=8.8Hz), 7.36 (s, 1H), 7.19 (s, 1H), 4.19 (m, 4H), 3.38 (m, 4H), 3.16 (t,2H, J=6.3 Hz), 2.28 (t, 2H, J=6.3 Hz); LCMS: ret. time: 12.85 min.;purity: 93.8%; MS (m/e): 673.35 (MH⁺). 7.3.164N2,N4-Bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950135) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) wasdissolved in a mixture of MeOH (1 ml) and H₂O (0.1 ml).3-amino-4-nitroaniline (184 mg, 1.2 mmol) was added and the mixture wasrefluxed for 3 days (70° C. oil-bath temperature). The mixture wascooled to 22° C., concentrated to dryness under reduced pressure andsubjected to column chromatography on silica gel (CHCl₃-Acetone, 2:1) togive N2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆ + CD₃OD): δ8.21 (d, 1H, J=2.9 Hz), 7.89 (m, 3H), 7.56 (d,1H, J=2.3 Hz), 7.01 (m, 1H), 6.81 (dd, 1H, J=2.3, 9.4 Hz); LCMS: purity:91.1%; MS (m/e): 401.00 (M⁺, 100). 7.3.165N2,N4-Bis(3-amino-2,4-difluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950138) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-2,4-difluoroaniline werereacted to prepareN2,N4-bis(3-amino-2,4-difluorophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 16.98 min.; purity: 91.7%; MS (m/e): 382.97 (MH⁺).7.3.166 N2,N4-Bis(3-amino-4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950139) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-4-ethoxyaniline were reactedto prepareN2,N4-bis(3-amino-4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 14.29 min.; purity: 93.4%; MS (m/e): 399.09 (MH⁺). 7.3.167N2,N4-Bis(3-amino-5-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950134) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-5-methoxycarbonylanilinewere reacted to prepareN2,N4-bis(3-amino-5-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 14.72 min.; purity: 93.8%; MS (m/e): 427.02 (MH⁺).7.3.168N2,N4-Bis(3-amino-5-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950140) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-5-trifluoromethylanilinewere reacted to prepareN2,N4-bis(3-amino-5-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.35 min.; purity: 100%; MS (m/e): 446.92 (MH⁺).7.3.169 N2,N4-Bis(3-amino-5-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950141) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-5-chloroaniline were reactedto prepareN2,N4-bis(3-amino-5-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 19.25 min.; purity: 99.3%; MS (m/e): 378.91 (MH⁺). 7.3.170N2,N4-Bis(4-hydroxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950093) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-hydroxy-3-trifluoromethylanilinewere reacted to prepareN2,N4-bis(4-hydroxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.06 min.; purity: 99.1%; MS (m/e): 448.88 (MH⁺).7.3.171 N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine HydrogenChloride salt (R950107)N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine was treated with2 equivalents of HCl in dioxane. The volatiles were removed underreduced pressure to giveN2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine hydrogenchloride salt. LCMS: ret. time: 9.74 min.; purity: 91.3%; MS (m/e):311.06 (MH⁺). 7.3.172N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine HydrogenChloride Salt (R950121)N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine was treated with2 equivalents of HCl in dioxane. The volatiles were removed underreduced pressure to giveN2,N4-bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine HydrogenChloride Salt. LCMS: ret. time: 11.15 min.; purity: 100%; MS (m/e):311.09 (MH⁺). 7.3.173 N2,N4-Bis(3-aminophenyl)-2,4-pyrimidinediamine(R950109) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-aminoaniline were reacted to prepareN2,N4-bis(3-aminophenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 8.90min.; purity: 91%; MS (m/e): 293.06 (MH⁺). 7.3.174N2,N4-Bis(3-amino-2,4-difluorophenyl)-2,4-pyrimidinediamine (R950131) Inlike manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-2,4-difluoroaniline were reacted toprepare N2,N4-bis(3-amino-2,4-difluorophenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 16.62 min.; purity: 96.7%; MS (m/e): 364.99 (MH⁺).7.3.175 N2,N4-Bis(3-amino-4-ethoxyphenyl)-2,4-pyrimidinediamine(R950142) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-4-ethoxyaniline were reacted toprepare N2,N4-bis(3-amino-4-ethoxyphenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 14.38 min.; purity: 99.7%; MS (m/e): 381.07 (MH⁺). 7.3.176N2,N4-Bis(3-amino-5-methoxycarbonylphenyl)-2,4-pyrimidinediamine(R950132) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-5-methoxycarbonylaniline were reactedto prepareN2,N4-bis(3-amino-5-methoxycarbonylphenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 15.25 min.; purity: 93.6%; MS (m/e): 409.02 (MH⁺). 7.3.177N2,N4-Bis(3-amino-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R950143) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-5-trifluoromethylaniline were reactedto prepareN2,N4-bis(3-amino-5-trifluoromethylphenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 23.23 min.; purity: 99.1%; MS (m/e): 428.95 (MH⁺). 7.3.178N2,N4-Bis(3-amino-5-chlorophenyl)-2,4-pyrimidinediamine (R950133) Inlike manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-5-chloroaniline were reacted toprepare N2,N4-bis(3-amino-5-chlorophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 19.45 min.; purity: 100%; MS (m/e): 360.93 (MH⁺). 7.3.179N2,N4-Bis[3-amino-4-(N-phenylamino)-phenyl]-5-fluoro-2,4-pyrimidinediamine(R950125) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-4-(N-phenylamino)-anilinewere reacted to prepareN2,N4-bis[3-amino-4-(N-phenylamino)-phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.67 min.; purity: 100%; MS (m/e): 476.36 (MH⁺).7.3.180N2,N4-Bis[3-amino-4-(N-phenylamino)-phenyl]-2,4-pyrimidinediamine(R950123) In like manner the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 3-amino-4-(N-phenylamino)-aniline werereacted to prepareN2,N4-bis[3-amino-4-(N-phenylamino)-phenyl]-2,4-pyrimidinediamine. LCMS:ret. time: 23.77 min.; purity: 77.8%; MS (m/e): 475.04 (MH⁺). 7.3.181N2,N4-Bis(5-amino-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950157) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-2-methylaniline were reactedto prepareN2,N4-bis(5-amino-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 10.61 min.; purity: 83.4%; MS (m/e): 339.13 (MH⁺). 7.3.182N2,N4-Bis(5-amino-2-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950158) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-2-fluoroaniline were reactedto prepareN2,N4-bis(5-amino-2-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 11.48 min.; purity: 95.6%; MS (m/e): 347.04 (MH⁺). 7.3.183N2,N4-Bis(3-amino-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950159) In like manner to the preparation ofN2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-amino-4-fluoroaniline were reactedto prepareN2,N4-bis(3-amino-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 18.74 min.; purity: 95.6%; MS (m/e): 347.29 (MH⁺). 7.3.184N2,N4-Bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950146) 2,4-Dichloro-5-fluoropyrimidine (33 mg, 0.2 mmol) wasdissolved in a mixture of MeOH (1 ml) and H₂O (0.1 ml).2-Methyl-5-nitroaniline (122 mg, 0.8 mmol) was added and the mixture wasrefluxed for 2 days (70° C. oil-bath temperature). The mixture wascooled to 22° C., concentrated to dryness under reduced pressure andsubjected to column chromatography on silica gel (CHCl₃-Acetone, 9:1) togive N2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆ + CD₃OD): δ8.31 (d, 1H, J=2.3 Hz), 8.20 (d, 1H, J=2.3Hz), 8.06 (d, 1H, J=3.5 Hz), 7.91 (dd, 1H, J=2.3, 8.2 Hz), 7.65 (dd, 1H,J=2.9, 8.8 Hz), 7.41 (m, 1H), 7.28 (d, 1H, J=8.2 Hz), 2.28 (s, 3H), 2.24(s, 3H); LCMS purity: 87.4%; MS (m/e): 399.20 (M⁺, 100). 7.3.185N2,N4-Bis(2-fluoro-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950147) In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-fluoro-5-nitroaniline were reactedto prepareN2,N4-bis(2-fluoro-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 31.07 min.; purity: 93.6%; MS (m/e): 407.14 (MH⁺). 7.3.186N2,N4-Bis(4-fluoro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950148) In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-nitroaniline were reactedto prepareN2,N4-bis(4-fluoro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 27.17 min.; purity: 94.3%; MS (m/e): 406.96 (MH⁺). 7.3.187N2,N4-Bis(4-methyl-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950144) In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-methyl-3-nitroaniline were reactedto prepareN2,N4-bis(4-methyl-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 27.40 min.; purity: 96.6%; MS (m/e): 399.00 (MH⁺). 7.3.188N2,N4-Bis(4-chloro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950149) In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-nitroaniline were reactedto prepareN2,N4-bis(4-chloro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 35.63 min.; purity: 98.9%; MS (m/e): 439.09 (MH⁺). 7.3.189N2,N4-Bis(2-hydroxyethyleneamino-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950150) In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and2-hydroxyethyleneamino-5-nitroaniline were reacted to prepareN2,N4-bis(2-hydroxyethyleneamino-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 17.90 min.; purity: 97.8%; MS (m/e): 489.19 (MH⁺).7.3.190N2,N4-Bis(2-methoxy-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950151) In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 2-methoxy-5-nitroaniline werereacted to prepareN2,N4-bis(2-methoxy-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 31.46 min.; purity: 95.9%; MS (m/e): 431.22 (MH⁺). 7.3.191N2,N4-Bis(4-fluoro-3-nitrophenyl)-2,4-pyrimidinediamine (R950152) Inlike manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 4-fluoro-3-nitroaniline were reacted toprepare N2,N4-bis(4-fluoro-3-nitrophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 30.92 min.; purity: 94.4%; MS (m/e): 389.31 (MH⁺). 7.3.192N2,N4-Bis(4-methyl-3-nitrophenyl)-2,4-pyrimidinediamine (R950153) Inlike manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 4-methyl-3-nitroaniline were reacted toprepare N2,N4-bis(4-methyl-3-nitrophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 31.22 min.; purity: 99.6%; MS (m/e): 381.35 (MH⁺). 7.3.193N2,N4-Bis(4-chloro-3-nitrophenyl)-2,4-pyrimidinediamine (R950154) Inlike manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 4-chloro-3-nitroaniline were reacted toprepare N2,N4-bis(4-chloro-3-nitrophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 37.24 min.; purity: 99.1%; MS (m/e): 421.30 (MH⁺). 7.3.194N2,N4-Bis(2-hydroxy-5-nitrophenyl)-2,4-pyrimidinediamine (R950155) Inlike manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 2-hydroxy-5-nitroaniline were reacted toprepare N2,N4-bis(2-hydroxy-5-nitrophenyl)-2,4-pyrimidinediamine. LCMS:ret. time: 23.26 min.; purity: 100%; MS (m/e): 385.33 (MH⁺). 7.3.195N2,N4-Bis(2-hydroxyethyleneamino-5-nitrophenyl)-2,4-pyrimidinediamine(R950156) In like manner to the preparation ofN2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloropyrimidine and 2-hydroxyethyleneamino-5-nitroaniline werereacted to prepareN2,N4-bis(2-hydroxyethyleneamino-5-nitrophenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 17.87 min.; purity: 97.2%; MS (m/e): 470.99 (MH⁺).7.3.196N2,N4-Bis[3-(N-isopropyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950166) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,acetone and sodiumcyanoborohydride were reacted together to giveN2,N4-bis[3-(N-isopropyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 14.07 min.; purity: 90.3%; MS (m/e): 395.14 (MH⁺).7.3.197N2,N4-Bis[3-N-(2-hydroxy-1-methylethyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950171) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,1-hydroxyacetone and sodiumcyanoborohydride were reacted to giveN2,N4-bis[3-N-(2-hydroxy-1-methylethyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 11.97 min.; purity: 79.01%; MS (m/e): 427.12 (MH⁺).7.3.198N2,N4-Bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950177) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine andtert-butyl bromoacetate were reacted together to giveN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 29.34 min.; purity: 97.2%; MS (m/e): 427.07 (MH⁺).7.3.199N4-(3-Aminophenyl)-N2-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950178) In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butylbromoacetate were reacted together to giveN4-(3-aminophenyl)-N2-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 18.33 min.; purity: 94.5%; MS (m/e): 369.09 (MH⁺).7.3.200N2-(3-Aminophenyl)-N4-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950179) In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butylbromoacetate were reacted together to giveN2-(3-aminophenyl)-N4-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 18.82 min.; purity: 85.8%; MS (m/e): 369.11 (MH⁺).7.3.201N2,N4-Bis(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950184) In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethylbromoacetate were reacted together to giveN2,N4-bis(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.41 min.; purity: 96.3%; MS (m/e): 483.08 (MH⁺).7.3.202N2,N4-Bis(3-ethoxycarbonylmethyleneaminophenyl)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-pyrimidinediamine(R950183) In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethylbromoacetate were reacted together to giveN2,N4-bis(3-ethoxycarbonylmethyleneaminophenyl)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 25.65 min.; purity: 92.5%; MS (m/e): 569.08 (MH⁺).7.3.203N2-(3-Aminophenyl)-N4-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamineandN4-(3-Aminophenyl)-N2-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950180) In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-bromo-2-hydroxyethane were reacted together to give a unseparablemixture ofN2-(3-aminophenyl)-N4-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamineandN4-(3-aminophenyl)-N2-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 9.84 min.; purity: 89.5%; MS (m/e): 355.10 (MH⁺).7.3.204N2,N4-Bis(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950181) In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-bromo-2-hydroxyethane were reacted together to giveN2,N4-bis(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 11.46 min.; purity: 83.3%; MS (m/e): 399.12 (MH⁺).7.3.205N2,N4-Bis[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950174) In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-benzyloxy-2-bromoethane were reacted together to giveN2,N4-bis[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 32.92 min.; MS (m/e): 579.17 (MH⁺). 7.3.206N2-(3-Aminophenyl)-N4-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950175) In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-benzyloxy-2-bromoethane were reacted together to giveN2-(3-aminophenyl)-N4-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.79 min.; MS (m/e): 445.11 (MH⁺). 7.3.207N4-(3-Aminophenyl)-N2-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R950176) In like manner to the preparation ofN2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and1-benzyloxy-2-bromoethane were reacted together to giveN4-(3-aminophenyl)-N2-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.64 min.; MS (m/e): 445.13 (MH⁺). 7.3.208N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926210) To a solution of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.028g, 0.1 mmol) in MeOH: H₂O (1.8: 0.2 mL) was added 3-hydroxyaniline(0.033 g, 0.3 mmol) and heated in a sealed tube at 100° C. for 24 h. Theresulting reaction was diluted with H₂O (10 mL), acidified with 2N HCl(pH >2), saturated and the resulting solid was filtered to give thedesired product,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl))-2,4-pyrimidinediamine(R926210). Purification can be done by filtration through a pad ofsilica gel using 1-5% MeOH in CH₂Cl₂ or by crystallization using anappropriate solvent system. ¹H NMR (CDCl₃ + CD₃OD): δ7.76 (bs, 1H), 7.30(d, 1H, J=2.4 Hz), 7.10 (m, 1H), 7.03 (t, 1H, J=8.1 Hz), 6.89 (dd, 2H,J=2.4 and 9 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.42 (dd, 1H, J=2.4 and 9 Hz),4.22 (m, 4H); ¹⁹F NMR (CDCl₃ + CD₃OD): - 47196; LCMS: ret. time: 19.55min.; purity: 95%; MS (m/e): 355 (MH⁺). Note: When the substrate hasethyl, butyl, benzyl etc. ester functions and the reaction is carriedout in methanol as a solvent, the cross esterification to produce methylester was observed. 7.3.209N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine(R925758) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.92 (d, 1H, J=3.0 Hz), 7.78 (bs, 1H), 7.41-7.31 (m,3H), 7.12 (d, 1H, J=7.2 Hz), 6.94 (bs, 1H), 6.81-6.75 (m, 3H), 4.68 (s,2H), 4.25 (s, 4H); ¹⁹F NMR (CDCl₃): - 47438; LCMS: ret. time: 17.73min.; purity: 100 %; MS (m/e): 369 (MH⁺). 7.3.210N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine(R925760) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.92 (bs, 1H), 7.62 (d, 2H, J=8.7 Hz), 7.36 (d, 2H,J=8.7 Hz), 7.19 (d, 1H, J=2.1), 6.87 (dd, 1H, J=2.7 and 8.7 Hz), 6.79(d, 1H, J=8.7 Hz), 4.68 (s, 2H), 4.28-4.23 (m, 4H); ¹⁹F NMR (CDCl₃): -4.7466; LCMS: ret. time: 17.86 min.; purity: 93 %; MS (m/e): 369 (MH⁺).7.3.211N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxy-2-phenylethyl)-2,4-pyrimidinediamine(R925765) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxy-2-phenylethyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.79 (s, 1H), 7.48 (m, 5H), 6.89-6.71 (m, 3H),5.41-5.38, 4.97 (dd, 1H, J=3.6 and 7.5 Hz), 4.28-4.22 (m, 4H), 3.88(ddd, 1H, J=4.2, 7.2, and 14.1), 3.64-3.55 (m, 1H); ¹⁹F NMR (CDCl₃): -47910; LCMS: ret. time: 20.47 min.; purity: 88 %; MS (m/e): 383 (MH⁺).7.3.212N2-(3,4-Ethylendioxyphenyl)-5-fluoro-N4-[(2R)-hydroxy-(1S)-methyl-2-phenylethyl)-2,4-pyrimidinediamine(R925766) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(2R)-hydroxy-(1S)-methyl-2-phenylethyl)-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylendioxyphenyl)-5-fluoro-N4-[(2R)-hydroxy-(1S)-methyl-2-phenylethyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.80 (bs, 1H), 7.71 (bs, 1H), 7.36-7.23 (m, 6H), 6.91(dd, 1H, J=3.0 and 9.0 Hz), 6.80 (d, 1H, J=9.0 Hz), 5.17 (d, 1H, J=8.1Hz), 5.01 (d, 1H, J=3.0 Hz), 4.56-4.50 (m, 1H), 4.24 (s, 4H), 1.10 (d,3H, J=6.3 Hz); ¹⁹F NMR (CDCl₃): - 47840; LCMS: ret. time: 21.43 min.;purity: 99 %; MS (m/e): 397 (MH⁺). 7.3.213N4-Cyclohexyl-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925794) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-cyclohexyl-5-fluoro-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN4-cyclohexyl-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.62 (d, 1H, J=4.2 Hz), 7.31 (d, 1H, J=2.1 Hz), 6.86(dd, 1H, J=2.4 and 8.7 Hz), 6.68 (d, 1H, J=8.7 Hz), 4.23-4.16 (m, 4H),3.99-3.89 (m, 1H), 2.03 (dd, 2H, J=2.1 and 12.3 Hz), 1.80 (dt, 2H, J=3.0and 13.5 Hz), 1.72-1.65 (m, 1H), 1.49-1.20 (m, 5H); ¹⁹F NMR (CD₃OD): -48332; LCMS: ret. time: 24.54 min.; purity: 95 %; MS (m/e): 345 (MH⁺).7.3.214N4-(4-Carboxycyclohexyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925795) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(4-carboxycyclohexyl)-2-chloro-5-fluoro-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN4-(4-carboxycyclohexyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.62 (d, 1H, J=4.2 Hz), 7.31 (d, 1H, J=2.4 Hz), 6.84(dd, 1H, J=2.4 and 8.7 Hz), 6.70 (d, 1H, J=8.7 Hz), 4.23-4.18 (m, 4H),3.99-4.08 (m, 1H), 2.59 (t, 1H, J=3.9 Hz), 2.16-2.09 (m, 2H), 1.91-1.84(m, 2H), 1.78-1.57 (m, 4H); ¹⁹F NMR (CD₃OD): - 48152; LCMS: ret. time:19.31 min.; purity: 96 %; MS (m/e): 389 (MH⁺). 7.3.215N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925796) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.30 (s, 1H), 9.12 (bs, 1H), 8.91 (bs, 1H), 8.02 (d,1H, J=3.3 Hz), 7.35-7.30 (m, 1H), 7.24-7.21 (m, 1H), 7.12 (t, 1H, J=1.8Hz), 7.09-7.04 (m, 2H), 6.67 (d, 1H, J=9.0), 6.46 (dd, 1H, J=1.8 and 8.4Hz), 4.18-4.12 (m, 4H); ¹⁹F NMR (DMSO-d₆): - 46594; LCMS: ret. time:18.43 min.; purity: 97 %; MS (m/e): 355 (MH⁺). 7.3.216N2-Allyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925823) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine andallylamine were reacted to yieldN2-allyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹HNMR (CD₃OD): δ7.71 (bs, 1H), 7.37 (d, 1H, J=2.4 Hz), 7.07 (dd, 1H, J=2.4and 8.7 Hz), 6.75 (d, 1H, J=8.7 Hz), 5.98-5.85 (m, 1H), 5.19 (dq, 1H,J=1.8 and 16.8 Hz), 5.06 (dq, 1H, J=1.8 and 10.5 Hz), 4.24-4.18 (m, 4H),3.92-3.68 (m, 2H); ¹⁹F NMR (CD₃OD): - 48552; LCMS: ret. time: 19.36min.; purity: 95 %; MS (m/e): 303 (MH⁺). 7.3.217N4-(3,4-Ethylenedioxyphenyl)-N2-(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926237) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-ethylaniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-N2-(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.87 (bs, 1H), 7.42 (d, 2H, J=8.7 Hz), 7.26 (d, 1H,J=3.0 Hz), 7.13-7.08 (m, 3H), 6.95 (dd, 1H, J=2.4 and 8.7 Hz), 6.82 (d,1H, J=9.0 Hz), 6.60 (bs, 1H), 4.23 (s, 4H), 2.59 (q, 2H, J=7.5 Hz), 1.20(t, 3H, J=7.5 Hz); ¹⁹F NMR (CDCl₃): - 47549; LCMS: ret. time: 25.31min.;purity: 99 %; MS (m/e): 367 (MH⁺). 7.3.218N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine(R926690) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-methoxycarbonyl-5-aminobenzofuran were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.68 (bs, 1H), 8.13-8.10 (m, 2H), 7.63-7.54 (m, 3H),7.27 (bs, 1H), 7.10 (d, 1H, J=8.7 Hz), 6.80 (d, 1H, J=8.1 Hz), 4.21 (s,4H), 3.88 (s, 3H); LCMS: ret. time: 23.22 min.; purity: 95 %; MS (m/e):437 (MH⁺). 7.3.2195-Fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine (R926704) In a manner similar to the preparationofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(isopropoxy)phenyl]-4-pyrimidineamine and2-methoxycarbonyl-5-aminobenzofuran were reacted to yield5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ8.04 (d, 1H, J=1.8 Hz),7.49-7.41 (m, 4H), 7.35 (dd, 1H, J=2.4 and 8.7 Hz), 7.14 (bs, 1H), 6.90(d, 2H, J=9.3 Hz), 6.70 (bs, 1H), 4.56 (2q, 1H, J=5.7 Hz), 3.98 (s, 3H),1.37 (d, 6H, J=5.7 Hz); LCMS: ret. time: 25.52 min.; purity: 98 %; MS(m/e): 437 (MH⁺). 7.3.220 5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine(R926376) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)]-4-pyrimidineamine and4-(2-hydroxyethyloxy)aniline were reacted to yield 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine.¹H NMR (D₂O): δ8.40 (d, 1H J=4 Hz), 7.57 (m, 6H), 7.12 (m, 2H), 6.90 (m,2H ), 4.40 (m, 4H) 2,2 (s, 3H); LCMS: ret. time: 13.61 min.; purity: 97%; MS (m/e): 357 (MH⁺). 7.3.221N2-[4-(2-N,N-Dimethylamino)ethoxyphenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R909236) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)]-4-pyrimidineamine and4-(2-N,N-dimethylamino)ethoxyaniline were reacted to yieldN2-[4-(2-N,N-dimethylamino)ethoxyphenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (CD₃OD): δ7.80 (d, 1H J=4Hz), 7.47 (dd, 1H, J=6.8 Hz, 2.7 Hz), 7.44 (m, 1H), 7.05 (m, 1H), 6.85(m, 1H), 6.78 (m, 2H), 4.16 (m, 2H), 3.03 (m, 2H), 2.55 (s, 6H); LCMS:ret. time: 12.74 min.; purity: 98 %; MS (m/e): 384 (MH⁺). 7.3.222N2-(1,4-Benzoxazin-3-on-6-yl)- 5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R909238) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)]-4-pyrimidineamine and6-amino-1,4-benzoxazin-3-one were reacted to yieldN2-(1,4-benzoxazin-3-on-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ8.18 (d, 1HJ=4 Hz), 7.17 (m, 3H), 7.09 (m, 1H ), 7.06 (m, 1H ), 6.58 (m, 1H) 4.52(s, 3H); LCMS: ret. time: 17.18 min.; purity: 99 %; MS (m/e): 368 (MH⁺).7.3.223N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R909241) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)]pyrimidineamine and6-amino-1,4-benzoxazine were reacted to yieldN2-(1,4-benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.82 (d, 1H, J=4 Hz), 7.15 (m, 3H), 6.68 (m, 2H), 6.52(m, 2H), 6.52 (m, 1H), 4.18 (m, 2H), 3.37 (m, 2H); LCMS: ret. time 17.42min.; purity: 95%; MS (m/e): 354 (MH⁺). 7.3.224N4-(1,4-Benzoxazin-6-yl)-N2-[3-ethoxyocarbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R909242) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3-ethoxyocarbonylmethyleneoxyaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.2 (d, 1H, J=4 Hz), 7.15 (m, 4H), 6.84 (m, 2H), 6.62(m, 1H), 4.65 (s, 2H), 4.15 (m, 4H), 3.28 (m, 2H), 1.19 (t, 3H. J=7 Hz);LCMS: ret. time 22.6 min.; purity: 94%; MS (m/e): 439 (MH⁺). 7.3.225N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R909243) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3-aminophenol were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ7.83 (d, 1H, J=4 Hz), 7.18 (m, 3H), 6.68 (m, 2H),6.45 (m, 2H), 6.52 (m, 1H), 4.22 (m, 2H), 3.31 (m, 2H); LCMS: ret. time:17.24; purity: 96%; MS (m/e): 354 (MH⁺). 7.3.226N4-(1,4-Benzoxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R909245) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3,5-dimethoxyaniline were reacted toyieldN4-(1,4-benzoxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.12 (d, 1H, J=4 Hz), 6.80 (m, 4H), 6.60 (m, 1H),6.05 (m, 1H), 4.02 (m, 2H), 3.65 (s, 6H), 3.31 (m, 2H); LCMS: ret. time:22.38 min.; purity: 99 %; MS (m/e): 398 (MH⁺). 7.3.227N4-(1,4-Benzoxazin-6-yl)-N2-(3-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine(R909246) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3-tert-butylaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-N2-(3-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.03 (d, 1H, J=4 Hz), 7.5 (m, 1H), 7.4 (m, 1H), 7.18(m, 1H), 7.02 (m, 1H), 6.80 (m, 2H), 6.60 (m, 1H), 4.02 (m, 2H), 3.31(m, 2H), 1.2 (s, 9H); LCMS: ret. time: 26.64 min.; purity: 99 %; MS(m/e): 508 (MH⁺). 7.3.228N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine(R909248) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and4-(2-hydroxyethyl)oxyaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ7.98 (d, 1H, J=4 Hz), 7.52 (m, 1H), 7.4 (m, 3H), 6.90(m, 2H), 6.68 (m, 1H), 4.56 (s, 2H), 4.02 (m, 2H), 3.75 (m, 2H), 3.31(m, 4H); LCMS: ret. time: 26.67 min.; purity: 93 %; MS(m/e): 399 (MH⁺).7.3.229N2-(2,3-Dihydrobenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R909250) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)]-4-pyrimidineamine and5-amino-2,3-dihydrobenzofuran were reacted to yieldN2-(2,3-dihydrobenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹HNMR (DMSO-d₆): δ8.09 (d, 1H), 8.00 (m, 1H), 7.82 (m, 1H), 7.57 (m,1H), 7.22 (m, 1H), 7.08 (m, 1H), 6.99 (m, 1H), 6.82 (m, 1H), 6.70 (m,1H), 6.42 (m, 1H), 4.49 (m, 2H), 3.15 (m, 2H); LCMS: ret time: 19.39min.; MS (m/e): 338 (MH⁺). 7.3.230N4-(1,4-Benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R909255) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-chloro-5-fluoro-4-pyrimidineamine and3-chloro-4-hydroxy-5-methylaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ7.89 (d, 1H, J=4 Hz), 7.25 (m, 1H), 7.14 (m, 1H),6.80 (m, 2H), 6.82 (m, 1H), 4.29 (s, 2H), 3.35 (m, 2H), 2.20 (s, 3H);LCMS: ret. time: 17.05 min.; purity: 99 %; MS(m/e): 402 (MH⁺). 7.3.2315-Fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R926706) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to yield5-fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.87 (d, 1H, J=3.0 Hz), 7.47-7.42 (m, 3H), 7.12 (dd,1H, J=2.4 and 8.4 Hz), 6.87 (d, 2H, J=9.6 Hz), 6.80 (d, 1H, J=8.7 Hz),6.63 (d, 1H, J=2.4 Hz), 5.21 (dd, 1H, J=6.3 and 10.5 Hz), 4.53 (2q, 1H,J=5.7 Hz), 3.80 (s, 3H), 3.52 (dd, 1H, J=10.5 and 15.9 Hz), 3.35 (dd,1H, J=6.3 and 15.9 Hz), 1.34 (d, 6H, J=5.7 Hz); ¹⁹F NMR (CDCl₃): -47664; LCMS: ret. time: 23.78 min.; purity: 95 %; MS (m/e): 439 (MH⁺).7.3.2325-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926699) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine and4-[2-(N-morpholino)ethyleneoxy]aniline were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.34 (s, 1H), 9.17 (bs, 1H), 8.95 (bs, 1H), 8.02 (d,1H, J=3.3 Hz), 7.53 (d, 2H, J=9.0 Hz), 7.28-7.23 (m, 1H), 7.12-7.04 (m,2H, 6.79 (d, 2H, J=9.0 Hz), 6.47 (dd, 1H, J=1.2 and 5.7 Hz), 4.00 (t,2H, J=6.0 Hz), 3.56 (t, 4H, J=4.5 Hz), 2.64 (t, 2H, J=6.0 Hz), 2.44 (t,4H, J=4.5 Hz); ¹⁹F NMR (DMSO-d₆): - 46715; LCMS: ret. time: 12.66 min.;purity: 95 %; MS (m/e): 426 (MH⁺). 7.3.233N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926709) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-[2-(N-morpholino)ethyleneoxy]aniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.80 (d, 1H, J=3.6 Hz), 7.72 (bs, 1H), 7.62 (bs, 1H),7.41 (d, 1H, J=9.3 Hz), 7.24 (d, 1H, J=5.4 Hz), 7.05 (dd, 1H, J=2.4 and8.7 Hz), 6.84 (d, 2H, J=8.7 Hz), 6.75 (d, 1H, J=9.0 Hz), 4.24 (bs, 4H),4.11 (t, 2H, J=5.4 Hz), 3.74-3.69 (m, 4H), 2.80 (t, 2H, J=5.4 Hz),2.62-2.58 (m, 4H); ¹⁹F NMR (CD₃OD): - 47912; LCMS: ret. time: 15.16min.; purity: 91 %; MS (m/e): 468 (MH⁺). 7.3.2345-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926710) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-4-pyrimidineamineand 3-aminophenol were reacted to yield5-fluoro-N2-(3-hydroxyphenyl)-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.84 (d, 1H, J=4.2 Hz), 7.60 (d, 1H. J=9.3 Hz), 7.09(t, 1H, J=2.4 Hz), 7.04-6.96 (m, 2H), 6.93 (d, 2H, J=9.3 Hz), 6.40 (dt,1H, J=1.8 and 7.5 Hz), 4.15 (t, 2H, J=5.4 Hz), 3.75-3.70 (m, 4H), 2.81(t, 2H, J=5.1 Hz), 2.63-2.59 (m, 4H); LCMS: ret. time: 14.16 min.;purity: 98 %; MS (m/e): 426 (MH⁺). 7.3.235N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926711) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to yieldN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.80 (d, 1H, J=4.2 Hz), 7.56 (d, 2H, J=8.7 Hz), 7.13(d, 1H, J=2.4 Hz), 6.91 (d, 2H, J=9.6 Hz), 6.86 (dd, 1H, J=2.4 and 9.0Hz), 6.67 (d, 1H, J=9.0 Hz), 4.23-4.18 (m, 4H), 4.14 (t, 3H, J=5.4 Hz),3.74-3.70 (m, 4H), 2.82 (t, 3H, J=5.4 Hz), 2.64-2.59 (m, 4H); ¹⁹F NMR(CDCl₃): - 47914; LCMS: ret. time: 15.97 min.; purity: 94 %; MS (m/e):468 (MH⁺). 7.3.236N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)phenyl]-2,4-pyrimidinediamine(R926716) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)aniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.11 (bs, 1H), 9.76 (bs, 1H), 8.19 (d, 1H, J=3.9Hz), 7.82 (d, 2H, J=8.7 Hz), 7.62 (d, 2H, J=8.7 Hz), 7.27 (d, 1H, J=2.4Hz), 7.08 (dd, 1H, J=2.4 and 8.7 Hz), 6.85 (d, 1H, J=8.7 Hz), 4.23 (s,4H), 3.10-3.06 (m, 4H), 1.64-1.58 (m, 4H); LCMS: ret. time: 22.68 min.;purity: 93 %; MS (m/e): 472 (MH⁺). 7.3.237N2-[3-[4-(2-Chloro-6-fluorobenzyl)piperazino]propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926717) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-[4-(2-chloro-6-fluorobenzyl)piperazino]propylamine were reacted toyieldN2-[3-[4-(2-chloro-6-fluorobenzyl)piperazino]propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.79 (d, 1H, J=3.0 Hz), 7.37 (d, 1H, J=2.4 Hz),7.19-7.15 (m, 2H), 7.00-6.93 (m, 2H), 6.81 (d, 1H, J=8.7 Hz), 6.56 (d,1H, J=2.7 Hz), 5.48 (bs, 1H), 4.27-4.21 (m, 4H), 3.70 (d, 2H, J=1.8 Hz),3.36 (q, 2H, J=6.3 Hz), 2.68-2.35 (m, 10H), 1.75 (q, 2H, J=6.3 Hz); ¹⁹FNMR (CDCl₃): - 31693, - 48483; LCMS: ret. time: 18.20 min.; purity: 97%; MS (m/e): 532 (MH⁺). 7.3.238N2-(4-tert-Butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine (R926719) In a manner similar to the preparationofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(4-tert -butylphenyl]-2-chloro-5-fluoro-4-pyrimidineamine and5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to yieldN2-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ10.16 (bs, 1H), 9.84 (bs, 1H),8.16 (d, 1H, J=5.4 Hz), 7.56 (d, 2H, J=8.1 Hz), 7.49 (s, 1H), 7.35 (d,2H, J=8.7 Hz), 7.13 (dd, 1H, J=1.8 and 8.7 Hz), 6.78 (d, 1H, J=8.7 Hz),5.35 (dd, 1H, J=6.6 and 10.5 Hz), 3.52 (dd, 1H, J=10.5 and 16.5 Hz),3.20 (dd, 1H, J=6.6 and 16.5 Hz), 1.27 (s, 9H); LCMS: ret. time: 26.52min.; purity: 96 %; MS (m/e): 437 (MH⁺). 7.3.239N4-[(5-Chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926721) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to yieldN4-[(5-chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.08 (d, 1H, J=1.8 Hz), 8.02 (d, 1H, J=8.7 Hz), 7.97(d, 1H, J=4.8 Hz), 7.63 (s, 1H), 7.42 (dd, 1H, J=1.8 and 9.3 Hz), 7.07(bs, 1H), 6.85 (dd, 1H, J=2.4 and 8.7 Hz), 6.56 (d, 1H, J=8.7 Hz), 4.77(s, 1H), 4.75 (s, 1H), 4.14 (s, 4H); LCMS: ret. time: 25.89 min.;purity: 97 %; MS (m/e): 444 (MH⁺). 7.3.240N4-[(5-Chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926722) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to yieldN4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.47 (bs, 1H), 9.33 (bs, 1H), 8.78 (bs, 1), 8.11 (d,1H, J=2.1 Hz), 8.02 (d, 1H, J=J=8.7 Hz), 7.98 (d, 1H, J=4.5 Hz), 7.69(s, 1H), 7.41 (dd, 1H, J=1.8, 8.1 Hz), 7.07 (bs, 1H), 6.92 (d, 1H, J=8.4Hz), 6.82 (t, 1H, J=8.1 Hz), 6.34 (d, 1H, J=6.9 Hz), 4.80 (s, 1H), 4.78(s, 1H); LCMS: ret. time: 23.32 min.; purity: 93 %; MS (m/e): 402 (MH⁺).7.3.241N4-[2-[(2-Chloro-6-fluorobenzyl)thio]ethyl]-N2-(3,4-ethylenedioxy)-5-fluoro-2,4-pyrimidinediamine(R926723) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-4-pyrimidineamineand 1,4-benzodioxan-6-amine were reacted to yieldN4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-N2-(3,4-ethylenedioxy)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.09 (bs, 1H), 7.94 (bs, 1H), 7.87 (d, 1H, J=4.2 Hz),7.34-7.30 (m, 2H), 7.24-7.18 (m, 2H), 7.01 (dd, 1H, J=2.4 and 8.7 Hz),6.68 (d, 1H, J=8.7 Hz), 4.11 (s, 4H), 3.83 (d, 2H, J=1.2 Hz), 3.63-3.56(m, 2H), 2.74 (t, 2H, J=7.5 Hz); LCMS: ret. time: 25.17 min.; purity: 92%; MS (m/e): 466 (MH⁺). 7.3.242N2-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945168) In a manner analogous to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2,3-dihydro-1,4-benzodioxin-6-ylmethylamine gaveN2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃) δ4.24 (s, 4 H), 4.45 (d, J=6.0 Hz, 2 H), 6.55 (ddd,J=0.9, 2.4 and 8.4 Hz, 1 H), 6.66 (d, 1 H), 6.84 (m, 4 H), 6.90 (m, 1H), 7.14 (t, J=8.1 Hz, 1 H), 7.30 (m, 1 H), 7.86 (d, J=3.3 Hz, 1 H); ¹⁹FNMR (282 MHz, CDCl₃) δ-170.44; LCMS: ret. time: 18.33 min.; purity:96.75%; MS (m/e): 369.03 (MH⁺). 7.3.243N4-[2-[(2-Chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926724) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to yieldN4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (methyl sulfoxide-d₆): δ9.76 (bs, 1H), 9.42 (bs, 1H), 8.70 (bs,1H), 8.02 (d, 1H, J=5.1 Hz), 7.33-7.30 (m, 2H), 7.24-7.18 (m, 1H),7.08-6.96 (m, 2H), 6.42 (d, 1H, J=4.6 Hz), 3.82 (d, 2H, J=1.2 Hz),3.68-3.61 (m, 2H), 2.77 (t, 2H, J=7.2 Hz); LCMS: ret. time: 23.00 min.;purity: 93 %; MS (m/e): 424 (MH⁺). 7.3.244N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-phenyl-5-methylisoxazol-4-yl)-2,4-pyrimidinediamine(R926743) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-methyl-3-phenyl-4-isoxazolamine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-phenyl-5-methylisoxazol-4-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 20.90 min.; purity: 96 %; MS (m/e): 420 (MH⁺). 7.3.245N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dimethylisoxazol-4-yl)-2,4-pyrimidinediamine(R926744) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,5-dimethyl-4-isoxazolamine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dimethylisoxazol-4-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.89 min.; purity: 98 %; MS (m/e): 358 (MH⁺). 7.3.246N2-[2-(Ethoxycarbonylmethylenethio)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926727) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-2-(ethoxycarbonylmethylenethio)pyridine were reacted to yieldN2-[2-(ethoxycarbonylmethylenethio)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.30 (s, 1H), 9.22 (s, 1H), 8.62 (d, 1H, J=2.4 Hz),8.06-8.01 (m, 2H), 7.25 (d, 1H, J=2.4 Hz), 7.18-7.14 (m, 2H), 6.80 (d,1H, J=6.0 Hz), 4.22 (bs, 4H), 4.07 (q, 2H, J=6.9 Hz), 3.95 (s, 2H), 1.14(t, 3H, J=6.9 Hz); LCMS: ret. time: 21.60 min.; purity: 97 %; MS (m/e):458(MH⁺). 7.3.247N2-[2-(Ethoxycarbonylmethyleneoxy)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926740) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-2-(ethoxycarbonylmethyleneoxy)pyridine were reacted to yieldN2-[2-(ethoxycarbonylmethyleneoxy)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.54 (bs, 1H), 9.14 (bs, 1H), 8.05 (s, 1H), 7.88 (d,1H, J=2.4 Hz), 7.54 (dd, 1H, J=2.7 and 10.2 Hz), 7.22 (d, 1H, J=1.8 Hz),7.10 (dd, 1H, J=1.8 and 8.7 Hz), 6.75 (d, 1H, J=9.0 Hz), 6.40 (d, 1H,J=9.9 Hz), 4.55 (s, 2H), 4.20 (bs, 4H), 4.10 (q, 2H, J=7.2 Hz), 1.18 (t,2H, J=7.2 Hz). 7.3.2485-Bromo-N2-(3,4-ethylenedioxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925797) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,5-bromo-2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yield5-bromo-N2-(3,4-ethylenedioxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ9.33 (s, 1H), 9.06 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H),7.13-7.06-(m, 4H), 6.94 (bs, 1H), 6.61 (d, 1H, J=8.7 Hz), 6.54-6.50 (m,1H), 4.17-4.13 (m, 4H); LCMS: ret. time: 20.01 min.; purity: 93 %; MS(m/e): 416 (MH⁺). 7.3.249N2-Allyl-5-bromo-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R925822) Ina manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,5-bromo-2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and allylaminewere reacted to yieldN2-allyl-5-bromo-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ8.08 (s, 1H), 7.21 (t, 1H, J=8.1 Hz), 7.02-6.97 (m, 2H), 6.71(dd, 1H, J=2.4 and 8.7 Hz), 5.91-5.77 (m, 1H), 5.19-5.09 (m, 2H),3.94-3.89 (m, 2H); LCMS: ret. time: 18.33 min.; purity: 99 %; MS (m/e):322 (MH⁺). 7.3.2505-Cyano-N2-(3,4-ethylenedioxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine(R925820) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-cyano-N4-( methoxycarbonylbenzyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to yield5-cyano-N2-(3,4-ethylenedioxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.23 (s, 1H), 7.41-7.32 (m, 5H), 7.01 (d, 1H, J=3.0Hz), 6.86-6.71 (m, 3H), 6.54 (bs, 1H), 5.48 (d, 1H, J=6.3 Hz), 4.31 (bs,4H), 3.68 (s, 3H); LCMS: ret. time: 25.53 min.; purity: 97 %; MS (m/e):418 (MH⁺). 7.3.251 (R935172):N4-[4-[Ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyanilinewere reacted to produceN4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J =3.5 Hz),7.70 (d, 2H, J =8.8 Hz), 7.29 (d, 1H, J =2.3 Hz), 7.23 (d, 2H, J =8.8Hz), 6.98 (dd, 1H, J =2.1 and 8.8 Hz), 6.66 (d, 1H, J =8.2 Hz),4.19-4.15 (m, 4H), 4.07 (qt, 2H, J =7.0 Hz), 1.48 (s, 6H), 1.10 (t, 3H,J =7.0 Hz). LCMS: ret. time: 24.51 min.; purity: 100%; MS (m/e): 453(MH⁺). 7.3.252 (R935173):N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-pyrimidine-2,4-diamine,N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewas reduced with DIBALH to giveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.23 (s, 1H), 8.94 (s, 1H), 8.01 (d, 1H, J =3.5 Hz),7.63 (d, 2H, J =8.8 Hz), 7.31-7.27 (m, 3H), 6.98 (dd, 1H, J=2.9 and 8.8Hz), 6.65 (d, 1H, J =8.8 Hz), 4.65 (t, 1H, J =5.3 Hz), 4.17-4.16 (m,4H), 3.39 (d, 2H, J =5.2 Hz), 1.20 (s, 6H). 8.9 Hz), LCMS: ret. time:19.52 min.; purity: 100%; MS (m/e): 411 (MH⁺). 7.3.253 R935182:5-Fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3,4-propylenedioxyphenyl)-4-pyrimidineamine and4-(methoxycarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.16 (s, 1H), 9.01 (s, 1H), 8.10 (d, 1H, J=4.1 Hz),7.51 (d, 2H, J=8.8 Hz), 7.37 (d, 1H, J=2.9 Hz), 7.32 (dd, 1H, J=2.9 and8.8 Hz), 6.98 (d, 1H, J=8.3 Hz), 6.80 (d, 2H, J=8.3 Hz), 4.70 (s, 2H),4.12-4.05 (app qt, 4H, J=5.3 Hz), 3.68 (s, 3H), 2.07 (q, 2H, J=5.3 Hz);LCMS: ret. time: 20.51 min.; purity: 97%; MS (m/e): 441 (MH⁺). 7.3.254R935185:5-Fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3,4-propylenedioxyphenyl)-4-pyrimidineamine and3-(methoxycarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.22 (s, 1H), 9.18 (s, 1H), 8.07 (d, 1H, J=3.5 Hz),7.41-7.35 (m, 2H), 7.32-7.28 (m, 2H), 7.09 (t, 1H, J=8.2 Hz), 6.90 (d,1H, J=8.2 Hz), 6.43 (dd, 1H, J=2.3 and 8.8 Hz), 4.65 (s, 2H), 4.11-4.04(app q, 4H, J=5.3 Hz), 3.67 (s, 3H), 2.06 (q, 2H, J=5.3 Hz); LCMS: ret.time: 20.57 min.; purity: 97%; MS (m/e): 441 (MH⁺). 7.3.255 R935187:N4-[3-(1-Bis(ethoxycarbonyl)ethoxy)phenyl]-5-fluoro-N2-[4-isopropoxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine and3-[1-bis(ethoxycarbonyl)ethoxy]aniline were reacted to provideN4-[3-(1-bis(ethyloxycarbonyl)ethoxy)phenyl]-5-fluoro-N2-[4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.08 (s, 1H), 9.98 (s, 1H), 8.19 (d, 1H, J=4.7 Hz),7.55 (d, 2H, J=8.8 Hz), 7.25 (d, 1H, J=8.8 Hz), 7.15 (d 1H, J=8.3 Hz),7.13 (d, 1H, J=8.3 Hz), 6.91 (d, 2H, J=8.8 Hz), 6.51 (dd, 1H, J=1.7 and8.3 Hz), 4.56 (q, 1H, J=5.8 Hz), 4.19 (qt, 4H, J=7.0 Hz), 1.61 (s, 3H),1.23 (d, 6H, J=5.8 Hz), 1.14 (t, 6H, J=7.0 Hz); LCMS: ret. time: 15.23min.; purity: 94%; MS (m/e): 527 (MH⁺). 7.3.256 R935190:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro -N2-(indazolin-6-yl) -2,4-pyrimidinediamine. In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and6-aminoindazole were reacted to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ9.69 (s,1H), 9.62 (s, 1H), 8.14 (d, 1H, J=4.7 Hz), 7.93 (s, 1H), 7.92 (s, 1H),7.60 (d, 1H, J=8.8 Hz), 7.33-7.31 (m 1H), 7.24 (dd, 2H, J=1.7 and 8.8Hz), 6.79 (d, J=8.8 Hz), 4.20 (s, 4H); LCMS: ret. time: 17.66 min.;purity: 99%; MS (m/e): 379 (MH⁺) 7.3.257 R935191:5-Fluoro-N4-(3-hydroxyphenyl)-N2-(indazolin-6-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine and5-aminoindazole were reacted to give 5-fluoroN4-(3-hydroxyphenyl)-N2-(indazolin-6-yl)-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ9.74 (s, 1H), 9.66 (s, 1H), 8.18 (d, 1H, J=4.1 Hz), 7.95 (s,1H), 7.93 (s, 1H), 7.59 (d, 1H, J=8.8 Hz), 7.33-7.26 (m, 2H), 7.12-7.07(m, 2H), 6.52 (dd, 1H, J=2.3 and 8.2 Hz); LCMS: ret. time: 15.27 min.;purity: 99%; MS (m/e): 337 (MH⁺) 7.3.258 R935193:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-imidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamime and1-methyl-5-aminoindazole were reacted to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.42 (s, 2H), 8.25 (d, 1H, J=5.2 Hz), 7.92 (s, 1H),7.86 (app s, 1H), 7.61 (d, 1H, J=8.8 Hz), 7.38 (dd, 1H, J=2.3 and9.3Hz), 7.21 (d, 1H, J=2.3 Hz), 7.09 (dd, 1H, J=2.3 and 8.8 Hz). 6.79(d, 1H, J=8.8 Hz), 4.20 (s, 4H), 4.02 (s, 3H); LCMS: ret. time: 19.09min.; purity: 99%; MS (m/e): 393 (MH⁺). 7.3.259 R935194:5-Fluoro-N4-(3-hydroxyphenyl)-N2-(1-methy-indazoline-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with1-methyl-5-aminoindazole to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-(1-methy-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.56 (s, 1H), 10.49 (s, 1H), 8.29 (d, 1H, J=5.2 Hz),7.98 (d, 1H, J=1.7 Hz), 7.92 (s, 1H), 7.59 (d, 1H, J=8.8 Hz), 7.36 (dd,1H, J=1.7 and 8.8 Hz), 7.10 (br m, 3H), 6.66 (td, 1H, J=1.7 and 7.0 Hz),4.01 (s, 3H). LCMS: ret. time: 16.62 min.; purity: 98%; MS (m/e): 351(MH⁺). 7.3.260 R935197:5-Fluoro-N2-(indazoline-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine:In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 5-aminoindazoline to produce5-fluoro-N2-(indazoline-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.. ¹H NMR (DMSO-d₆): δ9.96 (s, 1H), 9.76 (s, 1H), 8.12 (d, 1H, J=4.6 Hz),7.94 (s, 1H), 7.92 (s, 1H), 7.53 (d, 2H, J=9.8 Hz), 7.46 (d, 1H, J=8.8Hz), 7.34 (dd, 1H, J=1.7 and 9.8 Hz), 6.83 (d, 2H, J=9.8 Hz), 4.55 (q,1H, J=5.8 Hz), 1.24 (d, 6H, J=5.8 Hz). LCMS: ret. time: 18.96 min.;purity: 100%; MS (m/e): 379 (MH⁺). 7.3.261 R935198:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamime and5-aminoindazole were reacted to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.91 (s, 1H), 9.82 (s, 1H), 8.13 (d, 1H, J=4.6 Hz),7.94 (app s, 2H), 7.47 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=1.7 and 8.8Hz), 7.23 (d, 1H, J=2.3 Hz), 7.13(dd, 1H, J=2.3 and 8.8 Hz), 6.76 (d,1H, J=8.8 Hz), 4.20 (s, 4H); LCMS: ret. time: 16.17 min.; purity: 99%;MS (m/e): 379 (MH⁺). 7.3.262 R935199:5-Fluoro-N4-(3-hydroxyphenyl)-N2-(indazoline-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamime and5-aminoindazole were reacted to give5-fluoro-N4-(3-hydroxyphenyl)-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.78 (s, 1H), 9.68 (s, 1H), 9.49 (br s, 1H), 8.13 (d,1H, J=4.6 Hz), 8.06 (s, 1H), 7.93 (s, 1H), 7.50 (d, 1H, J=8.8 Hz), 7.38(dd, 1H, J=1.7 and 8.8 Hz), 7.17 (d, 1H, J=8.2 Hz), 7.11-7.06 (m, 2H),6.57 (dd, 1H, J=1.1 and 8.2 Hz). LCMS: ret. time: 13.79 min.; purity:96%; MS (m/e): 337 (MH⁺). 7.3.263 R935203:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine and4-isopropoxyaniline were reacted to produce5-fluoro-N2-(4-isopropoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.57 (s, 1H), 10.12 (s, 1H), 8.24 (d, 1H, J=5.3 Hz),8.04 (s, 1H), 7.95 (s, 1H), 7.63 (d, 1H, J=9.3 Hz), 7.55 (dd, 1H, J=1.7and 8.8 Hz), 7.30 (d, 2H, J=9.4 Hz), 6.82 (d, 2H, J=8.8 Hz), 4.53 (q,1H, J=6.4 Hz), 4.02 (s, 3H), 1.22 (d, 6H, J=6.4 Hz). LCMS: ret. time:20.56 min.; purity: 99%; MS (m/e): 393 (MH⁺). 7.3.264 R935204:5-Fluoro-N2-(3-hydroxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine and3-aminophenol were reacted to produce5-fluoro-N2-(3-hydroxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine..LCMS: ret. time: 15.55 min.; purity: 98%; MS (m/e): 351 (MH⁺). 7.3.265R935207:N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro- N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.48 (s, 1H), 9.41 (s, 1H), 8.08 (d, 1H, J=3.4 Hz),7.37-7.10 (m, 6H), 6.74 (d, 2H, J=8.2 Hz), 6.61 (d, 1H, J=8.2 Hz), 5.00(s, 2H), 4.19 (br s, 4H), 3.79 (s, 3H). LCMS: ret. time: 22.85 min.;purity: 97%; MS (m/e): 493 (MH⁺). 7.3.266 R935208:N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine wasreacted with 6-amino-1-(methoxycarbonyl)methyl-indazoline to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.39 (s, 1H), 9.19 (s, 1H), 8.08 (d, 1H, J=3.5 Hz),7.95 (s, 1H), 7.91 (s, 1H), 7.56 (d, 1H, J=8.2 Hz), 7.32 (d, 2H, J=8.9Hz), 7.22 (dd, 1H, J=2.9 and 8.2 Hz), 6.78 (d, 1H, J=8.8 Hz), 5.06 (s,2H), 4.21 (s, 4H), 3.61 (s, 3H). LCMS: ret. time: 19.39 min.; purity:93%; MS (m/e): 451 (MH⁺). 7.3.267 R935209:5-Fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine and4-(methoxycarbonylmethyleneoxy)aniline were reacted to provide5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 8.99 (s, 1H), 8.17 (s, 1H), 8.02 (d,1H, J=3.5 Hz), 7.92 (s, 1H), 7.59 (s, 2H), 7.50 (d, 2H, J=8.8 Hz), 6.73(d, 2H, J=8.8 Hz), 4.69 (s, 2H), 4.03 (s, 3H), 3.68 (s, 3H). LCMS: ret.time: 17.60 min.; purity: 99%; MS (m/e): 423 (MH⁺). 7.3.268 R935214:5-Fluoro-N2-(3,5-dimethoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methyl-indazoline-5-yl)-4-pyrimidineamine and3,5-dimethoxyaniline were reacted to produce5-fluoro-N2-(3,5-dimethoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.34 (s, 1H), 9.09 (s, 1H), 8.20 (d, 1H, J=5.3 Hz),8.07 (d, 1H, J=3.5 Hz), 7.90 (s, 1H), 7.63-7.55 (m, 2H), 6.89 (d, 2H,J=1.7 Hz), 6.02 (t, 1H, J=2.3 Hz), 4.02 (s, 3H), 3.54 (s, 6H). LCMS:ret. time: 18.81 min.; purity: 97%; MS (m/e): 395 (MH⁺). 7.3.269R935215:5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-1-(methoxycarbonyl)methyl-indazoline to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 16.08 min.; purity: 90%; MS (m/e): 408 (MH⁺). 7.3.270R935218:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-4-pyrimidineaminewas reacted with 4-isopropoxyaniline to provide5-fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.47 (s, 1H), 8.99 (s, 1H), 8.10 (s, 1H), 8.07 (d,1H, J=4.1 Hz), 8.02 (s, 1H), 7.68 (d, 1H, J=8.8 Hz), 7.50-7.46 (m, 3H),6.74 (d, 2H, 8.8 Hz), 5.26 (s, 2H), 4.47 (q, 1H, J=5.8 Hz), 3.62 (s,3H), 1.21 (d, 6H, J=5.8 Hz). LCMS: ret. time: 21.76 min.; purity: 97%;MS (m/e): 451 (MH⁺). 7.3.271 R935219:N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-4-pyrimidineaminewas reacted with 3,4-ethylenedioxyaniline to provideN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.48 (s, 1H), 9.01 (s, 1H), 8.10 (s, 1H), 8.09 (d,1H, J=3.5 Hz), 8.01 (s, 1H), 7.68 (d, 1H, J=8.8 Hz), 7.48-7.43 (m, 1H),7.29 (d, 1H, J=2.3 Hz), 6.99 (d, 1H, J=2.3 and 8.2 Hz), 6.67 (dd, 1H,J=2.3 and 8.8 Hz), 5.27 (s, 2H), 4.15 (s, 4H), 3.62 (s, 3H). LCMS: ret.time: 18.99 min.; purity: 93%; MS (m/e): 451 (MH⁺). 7.3.272 R935220:5-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-4-pyrimidineaminewas reacted with 3-aminophenol to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.51 (s, 1H), 9.19 (s, 1H), 9.10( s, 1H), 8.21 (s,1H), 8.12 (d, 1H, J=3.5 Hz), 8.02 (s, 1H), 7.68 (d, 1H, J=8.8 Hz),7.49-7.45 (m 1H), 7.16 (s, 1H), 7.09 (d, 1H, J=7.6 Hz), 6.95 (app t, 1H,J=7.6 and 8.2 Hz), 6.31 (dd, 1H, J=1.7 and 7.6 Hz), 5.29 (s, 2H), 3.62(s, 3H). LCMS: ret. time: 16.16 min.; purity: 97%; MS (m/e): 409 (MH⁺).7.3.273N4-(3,4-Ethylenedioxyphenyl)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine(R950203) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-aminomethylenefurane were reacted to giveN4-(3,4-ethylenedioxyphenyl)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 19.99 min.; purity: 88.4%; MS (m/e): 343.07 (MH⁺).7.3.274N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(4-methoxyphenyloxy)ethyl]-2,4-pyrimidinediamine(R950204) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-(4-methoxyphenyloxy)ethyl amine were reacted to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(4-methoxyphenyloxy)ethyl]-2,4-pyrimidinediamine.LCMS: ret. time: 22.74 min.; purity: 91.9%; MS (m/e): 413.05 (MH⁺).7.3.275N2-[2,3-Dihydrobenzo[b]furan-5-ylmethyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950205) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2,3-dihydrobenzo[b]furan-5-ylmethylamine were reacted to giveN2-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 21.43 min.; purity: 97.5%; MS (m/e): 395.05 (MH⁺).7.3.276N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950206) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to giveN2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.49 min.; purity: 87.6%; MS (m/e): 411.01 (MH⁺).7.3.277N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(methylthio)-1,3-benzothiaz-6-yl]-2,4-pyrimidinediamine(R950201) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-(methylthio)-1,3-benzothiazol-6-amine were reacted to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(methylthio)-1,3-benzothiaz-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 22.67 min.; purity: 76.9%; MS (m/e): 441.91 (MH⁺).7.3.278N2-[2,3-Dihydrobenzo[b]furan-5-ylmethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950213) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2,3-dihydrobenzo[b]furan-5-ylmethylamine were reacted toN2-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 17.80 min.; purity: 99.2%; MS (m/e): 353.08 (MH⁺).7.3.279N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950214) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to giveN2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.26 min.; purity: 96.2%; MS (m/e): 369.08 (MH⁺).7.3.2805-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methylthio)-1,3-benzothiaz-6-yl)-2,4-pyrimidinediamine(R950212) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2-(methylthio)-1,3-benzothiazol-6-amine were reacted to give5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methylthio)-1,3-benzothiaz-6-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.83 min.; purity: 98.9%; MS (m/e): 399.98 (MH⁺).7.3.281N2-(3-Aminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950227) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and1,3-diaminobenzene were reacted to giveN2-(3-aminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 11.89 min.; purity: 97.6%; MS (m/e): 312.05 (MH⁺).7.3.282N2-(1,4-Benzoxazin-6-yl)]-5-fluoro-N4-(3-nitrophenyl)-2,4-pyrimidinediamine(R950253) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and6-amino-1,4-benzoxazine were reacted to giveN2-(1,4-benzoxazin-6-yl)]-5-fluoro-N4-(3-nitrophenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.52 min.; purity: 99.5%; MS (m/e): 382.93 (MH⁺).7.3.283N2-(Ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950215) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-ethoxycarbonylmethyleneaminophenylaniline were reacted toN2-(ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.90 min.; purity: 83.4%; MS (m/e): 398.06 (MH⁺).7.3.284N2-(Ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(R950229) In like manner to the preparation ofN4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-ethoxycarbonylmethyleneaminophenylaniline were reacted toN2-(ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 16.37 min.; purity: 78.3%; MS (m/e): 441.03 (MH⁺).7.3.2855-Cyano-N2-(3-hydroxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine(R925821) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-cyano-N4-( methoxycarbonylbenzyl)-4-pyrimidineamine and3-hydroxyaniline were reacted to yield5-cyano-N2-(3-hydroxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.27 (s, 1H), 7.38-7.28 (m, 5H), 7.19-7.07 (m, 2H),6.98-6.91 (m, 2H), 6.64 (d, 1H, J=6.6 Hz), 3.55 (s, 3H); LCMS: ret.time: 24.18 min.; purity: 98 %; MS (m/e): 376 (MH⁺). 7.3.2865-Fluoro-N4-[2-fluoro-4-(methoxymethyleneoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926680) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-fluoro-4-methoxymethyleneoxyphenyl)-4-pyrimidineamineand 3-hydroxyaniline were reacted to yield5-fluoro-N4-(2-fluoro-4-methoxymethyleneoxyphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.7.3.287N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine(R926748) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-aminoindole were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 20.37 min.; purity: 97 %; MS (m/e): 378 (MH⁺). 7.3.2885-Fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine(R926749) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and5-aminoindole were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 17.31 min.; purity: 94 %; MS (m/e): 366 (MH⁺). 7.3.289N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926750) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and6-aminoindole were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 20.80 min.; purity: 91 %; MS (m/e): 378 (MH⁺). 7.3.2905-Fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926751) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and6-aminoindole were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.13 min.; purity: 96 %; MS (m/e): 336 (MH⁺). 7.3.291N4-[4-(Aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945063) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 3-hydroxyaniline (110 mg, 1 mmol) andN4-[4-(aminocarbonylmethyleneoxy)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(80 mg, 0.27 mmol) gaveN4-[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(75 mg, 76%). ¹H NMR (acetone-d ₆): δδ4.51 (s, 2 H), 6.64 (dm, J=8.4 Hz,1 H), 7.06-7.14 (m, 5 H), 7.70 (dd, J=2.4 and 9.0 Hz, 2 H), 8.27 (d,J=6.0 Hz, 1 H); ¹⁹F NMR (282 MHz, acetone-d ₆): δ- 164.00; LCMS: ret.time: 14.66 min.; purity: 88.63%; MS (m/e): 370.00 (MH⁺). 7.3.292N4-[4-(Cyanomethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945071) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-hydroxyaniline (94 mg, 0.86 mmol) and2-chloro-N4-[4-(cyanomethyleneoxy)phenyl]-5-fluoro-4-pyrimidineamine (80mg, 0.29 mmol) gaveN4-[4-(cyanomethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(65 mg, 64%) as a off-white solid. ¹H NMR (acetone-d ₆): δ5.16 (s, 2 H),6.64 (ddd, J=1.8, 2.4 and 7.5 Hz, 1 H), 7.03 (t, J=2.1 Hz, 1 H),7.08-7.16 (m, 2 H), 7.19 (d, J=9.3 Hz, 2 H), 7.77 (d, J=9.3 Hz, 2 H),8.30 (d, J=5.4 Hz, 1 H), 10.04 (s, 1 H, NH), 11.33 (s, 1 H, NH); ¹⁹F NMR(282 MHz, acetone-d ₆): δ- 163.52; LCMS: ret. time: 17.08 min.; purity:100%; MS (m/e): 352.13 (MH⁺). 7.3.293N4-(3-Cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945109) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-aminobenzonitrile (142 mg, 1.2 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (128 mg, 86%) asa white solid. The reaction of2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol)and 3-aminophenol (66 mg, 0.6 mmol) gaveN4-(3-cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(40 mg, 62%). ¹H NMR (acetone-d ₆): δ6.48 (ddd, J=0.9, 2.4 and 7.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1 H), 7.18 (ddd, J=1.2, 2.1 and 8.1 Hz, 1 H),7.33 (t, J=2.1 Hz, 1 H), 7.45 (dt, J=1.2 and 7.8 Hz, 1 H), 7.54 (t,J=8.1 Hz, 1 H), 8.08 (d, J=3.3 Hz, 1 H), 8.14 (ddd, J=1.5, 2.7 and 8.4Hz, 1 H), 8.39 (t, J=2.1 Hz, 1 H), 8.58 (s, 1 H, NH), 8.84 (s, 1 H, NH);¹⁹F NMR (282 MHz, acetone-d ₆): δ- 167.41; LCMS: ret. time: 17.75 min.;purity: 92.39%; MS (m/e): 322.59 (MH⁺). 7.3.294N4-(3-Cyanophenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945110) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol)and 4-(methoxycarbonylmethyleneoxy)aniline (109 mg, 0.6 mmol) gaveN4-(3-cyanophenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(30 mg, 38%). ¹H NMR (acetone-d ₆): δ3.74 (s, 3 H), 4.72 (s, 2 H), 6.93(d, J=9.0 Hz, 2 H), 7.46 (dt, J=1.5 and 7.5 Hz, 1 H), 7.54 (t, J=7.8 Hz,1 H), 7.60 (dd, J=1.8 and 9.0 Hz, 2 H), 8.03-8.07 (m, 2 H), 8.43 (m, 1H), 8.48 (br, 1 H, NH), 8.80 (br, 1 H, NH); ¹⁹F NMR (282 MHz, acetone-d₆): δ-168.2; LCMS: ret. time: 20.24 min.; purity: 94.79%; MS (m/e):393.98 (MH⁺). 7.3.2955-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(indol-3-yl)ethyl]-2,4-pyrimidinediamine(R945117) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and tryptamine (100 mg, 0.62 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(indol-3-yl)ethyl]-2,4-pyrimidinediamine(40 mg, 53%). ¹H NMR (CD₃OD): δ3.01 (t, J=7.2 Hz, 2 H), 3.61 (t, J=7.2Hz, 2 H), 6.51 (ddd, J=0.9, 2.1 and 8.1 Hz, 1 H), 6.96 (td, J=0.9 and7.2 Hz, 1 H), 7.03-7.09 (m, 3 H), 7.22 (d, J=7.5 Hz, 1 H), 7.28-7.32 (m,2 H), 7.53 (d, J=7.8 Hz, 1 H), 7.72 (d, J=4.5 Hz, 1 H); ¹⁹F NMR (282MHz, CD₃OD): δ- 171.72; LCMS: ret. time: 20.17 min.; 95.66%; MS (m/e):364.05 (MH⁺). 7.3.2965-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945118) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(80 mg, 0.33 mmol) and 3-methoxycarbonylmethyleneoxyaniline (180 mg,0.99 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(130 mg). ¹H NMR (acetone-d ₆): δ3.74 (s, 3 H), 4.64 (s, 2 H), 6.71 (m,1 H), 6.80 (m, 1 H), 7.23-7.32 (m, 6 H), 8.32 (d, J=5.1 Hz, 1 H); LCMS:ret. time: 18.37 min.; purity: 100%; MS (m/e): 384.70 (MH⁺). 7.3.297N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945124) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (80 mg,0.28 mmol) and 3-methoxycarbonylmethyleneoxyaniline (154 mg, 0.85 mmol)gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(90 mg, 74%). ¹H NMR (CDCl₃): δ3.80 (s, 3H), 4.27 (q, J=0.9 Hz, 4H),4.58 (s, 2H), 6.54 (ddd, J=0.9, 2.7 and 8.1 Hz, 1H), 6.65 (d, J=2.7 Hz,1H), 6.86 (d, J=8.7 Hz, 1H), 6.98 (dd, J=2.4 and 8.4 Hz, 1H), 6.98 (br,1 H), 7.09 (ddd, J=1.2, 2.1 and 8.1 Hz, 1H), 7.18 (t, J=8.1 Hz, 1H),7.24 (d, J=2.4 Hz, 1H), 7.32 (t, J=2.1 Hz, 1H), 7.92 (d, J=3.3 Hz, 1H);¹⁹F NMR (282 MHz, CDCl₃): δ- 167.52; LCMS: ret. time: 21.64 min.;purity: 98.07%; MS (m/e): 426.99 (MH⁺). 7.3.2985-Fluoro-N4-(4-isopropoxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945125) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine (80 mg, 0.28mmol) and methyl 3-aminophenoxyacete (154 mg, 0.85 mmol) gave5-fluoro-N4-(4-isopropoxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(80 mg, 66%). ¹H NMR (CDCl₃) δ1.33 (s, 3H), 1.35 (s, 3H), 3.80 (s, 3H),4.52 (p, J=6.0 Hz, 1H), 4.55 (s, 2H), 6.53 (ddd, J=0.9, 2.4 and 8.1 Hz,1H), 6.69 (d, J=2.4 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 7.04-7.08 (m, 2H),7.16 (t, J=8.1 Hz, 1H), 7.32 (t, J=2.1 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H),7.92 (d, J=3.0 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 167.64; LCMS: ret.time: 24.70 min.; purity: 100%; MS (m/e): 427.00 (MH⁺). 7.3.299N2-[4-(Aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945064) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl))-5-fluoro-2,4-pyrimidinediamine,4-(aminocarbonylmethyleneoxy)aniline (198 mg, 1.2 mmol) and2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (95 mg, 0.4mmol) gaveN2-[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(60 mg, 41%). ¹H NMR (CD₃OD): δ4.55 (s, 2H), 6.75 (dm, J=7.5 Hz, 1H),7.08 (d, J=9.3 Hz, 2H), 7.18 (m, 2H), 7.22 (d, J=8.7 Hz, 1H), 7.46 (d,J=9.0 Hz, 2H), 8.09 (d, 1H); LCMS: ret. time: 14.38 min.; purity: 100%;MS (m/e): 370.00 (MH⁺). 7.3.3005-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945132) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline(490 mg, 2.4 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2mmol) gave2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine.The reaction of2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(40 mg, 0.12 mmol) and 3-aminophenol (40 mg, 0.36 mmol) gave5-fluoro-N2-(3-hydroxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(30 mg, 62%). ¹H NMR (CDCl₃): δ2.61 (s, 3H), 5.21 (s, 2H), 6.50 (ddd,J=0.9, 2.4 and 7.8 Hz, 1H), 6.76 (ddd, J=0.6, 2.4 and 9.0 Hz, 1H),6.80-6.85 (m, 3H), 7.12 (t, J=8.1 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H),7.50-7.52 (m, 2H), 7.94 (d, J=3.3 Hz, 1H), 7.98 (t, J=2.4 Hz, 1H); ¹⁹FNMR (282 MHz, CDCl₃): δ- 167.19; LCMS: ret. time: 18.88 min.; purity:100%; MS (m/e): 408.97 (MH⁺). 7.3.301N2-[4-(Aminocarbonylmethoxy)phenyl]-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945133) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(30 mg, 0.09 mmol) and 4-(aminocarbonylmethyleneoxy)aniline (45 mg, 0.27mmol) gaveN2-[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(10 mg, 24%). ¹H NMR (acetone-d ₆): δ2.62 (s, 3H), 4.43 (s, 2H), 5.19(s, 2H), 6.77 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H),7.25 (t, J=8.1 Hz, 1H), 7.34 (ddd, J=0.9, 1.8, 9.0 Hz, 1H), 7.68 (d,J=9.0 Hz, 2H), 7.81 (t, J=2.1 Hz, 1H), 7.99 (d, J=3.6 Hz, 1H), 8.45 (br,1H, NH), 8.57 (br, 1H, NH); ¹⁹F NMR (282 MHz, acetone-d ₆): δ- 168.20;LCMS: ret. time: 16.80 min.; purity: 84.91%; MS (m/e): 466.05 (MH⁺).7.3.302N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945128) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (40 mg,0.14 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (87mg, 0.42 mmol) gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(30 mg, 47%). ¹H NMR (CDCl₃): δ2.62 (s, 3H), 4.26 (q, J=2.1 Hz, 4H),5.09 (s, 2H), 6.63-6.67 (m, 2H), 6.85 (d, J=8.4 Hz, 1H), 6.95-6.99 (m,2H), 7.09 (dt, J=0.9 and 6.9 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H), 7.23 (d,J=2.4 Hz, 1H), 7.42 (t, J=2.4 Hz, 1H), 7.92 (d, J=3.0 Hz, 1H); ¹⁹F NMR(282 MHz, CDCl₃): δ-167.47; LCMS: ret. time: 21.26 min.; purity: 96.72%;MS (m/e): 451.01 (MH⁺). 7.3.3035-Fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945129) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine (40 mg, 0.14mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (87 mg,0.42 mmol) gave5-fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(40 mg, 63%). ¹H NMR (CDCl₃): δ1.32 (s, 3H), 1.34 (s, 3H), 2.61 (s, 3H),4.52 (p, J=6.0 Hz, 1H), 5.08 (s, 2H), 6.64 (ddd, J=1.2, 2.7 and 8.1 Hz,1 H), 6.70 (d, J=2.4 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 7.07-7.11 (m, 2H),7.16 (t, J=8.1 Hz, 1H), 7.38 (t, J=2.1 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H),7.91 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 167.55; LCMS: ret.time: 24.49 min.; 96.15%; MS (m/e): 451.08 (MH⁺). 7.3.304N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945137) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(40 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (55 mg, 0.36 mmol)reacted to giveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ2.60 (s, 3H), 4.24 (q, J=2.7 Hz, 4H), 5.21 (s, 2H),6.74-6.78 (m, 2H), 6.81 (d, J=8.4 Hz, 1H), 6.90 (dd, J=1.2, 7.8 Hz, 1H),7.01 (dd, J=2.4 and 8.4 Hz, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.30 (d, J=2.4Hz, 1H), 7.48 (br, 1H), 7.94 (d, J=3.3 Hz, 1H), 7.98 (br, 1H); ¹⁹F NMR(282 MHz, CDCl₃) δ- 168.23; LCMS: ret. time: 21.20 min.; purity: 91.09%;MS (m/e): 450.99 (MH⁺). 7.3.3055-Fluoro-N2-(4-isopropoxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945138) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(40 mg, 0.12 mmol) and 4-isopropoxyaniline (55 mg, 0.36 mmol) gave5-fluoro-N2-(4-isopropoxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.31 (s, 3H), 1.33 (s, 3H), 2.60 (s, 3H), 4.48 (p,J=6.0 Hz, 1H), 5.20 (s, 2H), 6.74-6.78 (m, 2H), 6.87 (d, J=9.0 Hz, 2H),6.92 (dd, J=1.2 and 8.4 Hz, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.50 (m, 3H),7.94 (d, J=3.0 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 168.46; LCMS: ret.time: 24.95 min.; purity: 73.74%; MS (m/e): 451.06 (MH⁺). 7.3.306N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945139) Using general hydrogenation conditions,2,6-dimethyl-4-nitrophenol was reduced to 4-amino-2,6-dimethylphenol. Ina manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 4-amino-2,6-dimethylphenol (823 mg, 6 mmol) and2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) gave2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine.Compound2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine(500 mg, 1.87 mmol) and 3-(methoxycarbonylmethyleneoxy)aniline (500 mg,2.76 mmol) reacted to giveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(500 mg, 65%). ¹H NMR (CD₃OD): δ2.16 (s, 6H), 3.76 (s, 3H), 4.51 (s,2H), 6.79 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 7.01-7.06 (m, 2H), 7.15 (s,2H), 7.26 (t, J=8.1 Hz, 1H), 7.93 (d, J=5.7 Hz, 1H); ¹⁹F NMR (282 MHz,CD₃OD): δ- 163.31; LCMS: ret. time: 20.44 min.; purity: 84.25%; MS(m/e): 413.03 (MH⁺). 7.3.307N4-(Benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945146) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gaveN4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. Thereaction ofN4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and3-aminophenol (200 mg, 1.83 mmol) gaveN4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.(40 mg, 36%). ¹H NMR (CDCl₃): δ4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85(ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H),7.26 (m, 1H), 7.39-7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84(d, J=3.3 Hz, 1H), 7.92 (m, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 168.89;LCMS: ret. time: 21.91 min.; purity: 99.34%; MS (m/e): 366.96 (MH⁺).7.3.3085-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine(R945147) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gaveN4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. Thereaction ofN4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and3-aminophenol (200 mg, 1.83 mmol) gaveN4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.(40 mg, 36%). ¹H NMR (CDCl₃): δ4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85(ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H),7.26 (m, 1H), 7.39-7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84(d, J=3.3 Hz, 1H), 7.92 (m, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 168.89;LCMS: ret. time: 21.91 min.; purity: 99.34%; MS (m/e): 366.96 (MH⁺).7.3.3085-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine(R945147) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-pyridylmethylamine (162 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) were reacted to give2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine. Then2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine and3-aminophenol (200 mg, 1.83 mmol) reacted to give5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine(40 mg, 43%). ¹H NMR (CD₃OD): δ4.71 (s, 2H), 6.38 (ddd, J=0.9, 2.4 and8.1 Hz, 1H), 6.88 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 7.00 (t, J=8.1 Hz,1H), 7.14 (t, J=2.4 Hz, 1H), 7.37 (dd, J=4.8 and 7.8 Hz, 1H), 7.73 (d,J=3.6 Hz, 1H), 7.87 (dt, J=2.1 and 7.5 Hz, 1H), 8.39 (dd, J=1.2 and 7.8Hz, 1H), 8.57 (d, J=2.1 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ- 170.99;LCMS: ret. time: 8.82 min.; purity: 92.90%; MS (m/e): 312.05 (MH⁺).7.3.309N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945148) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-amino-2-chloro-6-methylphenol and 2,4-dichloro-5-fluoropyrimidineresulted2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine.The reaction of2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamineand 3-methoxycarbonylmethyleneoxyaniline (1.95 g, 11 mmol) gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(850 mg, 55%). ¹H NMR (CD₃OD): δ2.22 (s, 3H), 3.76 (s, 3H), 4.52 (s,2H), 6.50 (dt, J=2.7 and 6.3 Hz, 1H), 7.09-7.14 (m, 2H), 7.24 (t, J=1.8Hz, 1H), 7.30 (t, J=1.2 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.88 (d, J=3.9Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ- 168.70; LCMS: ret. time: 20.63min.; purity: 98.56%; MS (m/e): 432.96 (MH⁺). 7.3.310N4-[(2,5-Dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945151) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of (2,5-dimethyl-3-furyl)methylamine (188 mg, 1.5 mmol) and2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine.The reaction of2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamineand 3-aminophenol (200 mg, 1.83 mmol) gaveN4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(50 mg, 51%). ¹H NMR (CDCl₃): δ2.22 (s, 3H), 2.23 (s, 3H), 4.39 (d,J=5.1 Hz, 2H), 5.24 (br, 1H), 5.90 (s, 1H), 6.52 (d, J=6.6 Hz, 1H), 6.99(d, J=8.1 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.71 (m, 2H);¹⁹F NMR (282 MHz, CDCl₃): δ- 167.84; LCMS: ret. time: 19.83 min.;purity: 96.32%; MS (m/e): 329.05 (MH⁺). 7.3.311N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945153) In a manner analogous to the preparation ofN2,N4-bis[3-methoxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine,the reaction of 2,6-dimethyl-4-nitrophenol (1.67 g, 10 mmol), potassiumcarbonate (13 g, 0.1 mol) and iodomethane (2.5 mL, 50 mmol) gave2,6-dimethyl-1-methoxy-4-nitrobenzene. Hydrogenation of2,6-dimethyl-1-methoxy-4-nitrobenzene gave3,5-dimethyl-4-methoxyaniline. In a manner analogous to the preparationofN4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,the reaction of 3,5-dimethyl-4-methoxyaniline (400 mg, 2.6 mmol) and2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) gave2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine.The reaction of2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamineand 3-(methoxycarbonylmethyleneoxy)aniline (650 mg, 3.6 mmol) gaveN4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(180 mg, 35%). ¹H NMR (CD₃OD): δ2.20 (s, 6H), 3.70 (s, 3H), 3.74 (s,3H), 4.52 (s, 2H), 6.76 (ddd, J=0.9, 2.4 and 8.4 Hz, 1H), 7.03-7.08 (m,2H), 7.24 (m, 3H), 7.96 (d, J=5.4 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ-162.92; LCMS: ret. time: 23.13 min.; purity: 100%; MS (m/e): 427.04(MH⁺). 7.3.312N4-[4-(N-Benzylpiperazino)phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945155) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction ofN4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(50 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (0.045 mL, 0.36 mmol)gaveN4-[4-(N-benzylpiperazino)phenyl)]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(40 mg, 63%). ¹H NMR (CDCl₃): δ2.64 (t, J=4.8 Hz, 4H), 3.20 (t, J=4.8Hz, 4H), 3.59 (s, 2H), 4.24 (m, 4H), 6.61 (d, 1H, NH), 6.68 (br, 1H,NH), 6.76 (d, J=8.7 Hz, 1H), 6.88 (dd, J=2.4 and 8.7 Hz, 1H), 6.93 (d,J=8.7 Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.28-7.36 (m, 5H), 7.47 (d, J=8.7Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ-168.66;LCMS: ret. time: 18.05 min.; purity: 100%; MS (m/e): 513.10 (MH⁺).7.3.313N2-[(2,5-Dimethyl-3-furyl)methyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945162) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and (2,5-dimethyl-3-furyl)methylamine (80 mg, 0.63mmol) gaveN2-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(40 mg, 59%). ¹H NMR (acetone-d ₆): δ2.14 (s, 6H), 4.37 (d, J=4.2 Hz,2H), 5.96 (s, 1H), 6.77 (d, J=6.6 Hz, 1H), 7.23-7.28 (m, 2H), 7.44 (s,1H), 8.11 (d, J=4.8 Hz, 1H), 9.05 (br, 1H), 9.75 (br, 1H); ¹⁹F NMR (282MHz, acetone-d ₆): δ- 165.77; LCMS: ret. time: 19.23 min.; purity:94.89%; MS (m/e): 329.08 (MH⁺). 7.3.314N2-[4-(N-Benzylpiperazino)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945163) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylendioxyphenyl)-5-fluoro-4-pyrimidineamine (50 mg,0.18 mmol) and 4-(4-benzylpiperazino)aniline (142 mg, 0.53 mmol)resultedN2-[4-(N-benzylpiperazino)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(30 mg, 33%). ¹H NMR (CDCl₃): δ2.63 (t, J=4.8 Hz, 4H), 3.16 (t, J=4.8Hz, 4H), 3.58 (s, 2H), 4.27 (m, 4H), 6.56 (d, 1H, NH), 6.70 (br, 1H,NH), 6.82 (d, J=8.7 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 6.96 (dd, J=2.7 and8.7 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.30-7.36 (m, 5H), 7.39 (d, J=8.7Hz, 2H), 7.88 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 168.94;LCMS: ret. time: 18.12 min.; purity: 98.42%; MS (m/e): 512.95 (MH⁺).7.3.315N2-(Benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945164) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and benzothiophen-3-ylmethylamine (100 mg, 0.61 mmol)gaveN2-(benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(40 mg, 53%). ¹H NMR (CDCl₃): δ4.82 (d, J=6.0 Hz, 2H), 6.45 (dd, J=8.1Hz, 1H), 6.70 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.03 (t, J=8.1 Hz, 1H),7.22 (m, 1H), 7.34 (s, 1H), 7.39-7.46 (m, 2H), 7.82 (m, 1H), 7.89-7.92(m, 2H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 170.02; LCMS: ret. time: 21.29min.; purity: 92.97%; MS (m/e): 367.03 (MH⁺). 7.3.3165-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine(R945165) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and 3-pyridylmethylamine (68 mg, 0.63 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine(40 mg, 62%). ¹H NMR (CDCl₃): δ4.40 (d, J=6.3 Hz, 2H), 5.60 (br, 1H),6.62-6.70 (m, 3H), 7.05 (br, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.30 (dd,J=5.1 and 7.8 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.80 (d, J=3.3 Hz, 1H),8.49 (d, J=4.5 Hz, 1H), 8.66 (s, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ-169.52; LCMS: ret. time: 9.41 min.; purity: 99.25%; MS (m/e): 312.01(MH⁺). 7.3.3175-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine(R945166) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(50 mg, 0.21 mmol) and 2-pyridylmethylamine (68 mg, 0.63 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine(40 mg, 62%). ¹H NMR (CDCl₃): δ4.73 (d, J=6.3 Hz, 2H), 5.85 (t, J=6.0Hz, 1H, NH), 6.48 (d, J=6.9 Hz, 1H), 6.61 (dd, J=2.7 and 8.1 Hz, 1H),6.67 (s, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.21 (dd, J=5.1 and 7.5 Hz, 1H),7.49 (d, J=7.5 Hz, 1H), 7.69 (td, J=1.8 and 7.8 Hz, 1H), 7.85 (d, J=3.6Hz, 1H), 8.38 (br, 1H), 8.56 (dd, J=1.2 and 3.9 Hz, 1H); ¹⁹F NMR (282MHz, CDCl₃): δ-170.49; LCMS: ret. time: 10.10 min.; purity: 100%; MS(m/e): 312.08 (MH⁺). 7.3.318N4-(3,5-Dimethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926802) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with3-hydroxyaniline gaveN4-(3,5-dimethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 18.98 min.; purity: 90%; MS (m/e): 357 (MH⁺). 7.3.319N4-(3,5-Dimethoxyphenyl)-N2-(2-ethoxycarbonylindol-7-yl)-5-fluoro-2,4-pyrimidinediamine(R926803) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with2-ethoxycarbonyl-7-aminoindole gaveN4-(3,5-dimethoxyphenyl)-N2-(2-ethoxycarbonylindol-7-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 24.21 min.; purity: 91%; MS (m/e): 452 (MH⁺). 7.3.320N2-(3,4-Dimethoxyphenyl)-N4-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926108) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3,4-dimethoxyaniline gaveN2-(3,4-dimethoxyphenyl)-N4-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.89 (d, 1H, J=3 Hz), 7.45 (bd, 2H, J=9 Hz), 7.20 (d,1H, J=2.4 Hz), 6.96-6.77 (m, 5H), 6.63 (bs, 1H), 4.03 (q, 2H, J=7.2 Hz),3.86 (s, 3H), 3.72 (s, 3H), 1.42 (t, 3H, J=7.2 Hz); ¹⁹F NMR (CDCl3): -47473. 7.3.321N4-(4-Ethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926146) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3-hydroxyaniline gaveN4-(4-ethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.79 (d, 1H, J=4.2 Hz), 7.54 (dd, 2H, J=2.4 and 7.2Hz), 7.05-6.97 (m, 3H), 6.87 (dd, 2H, J=2.4 and 4.2 Hz), 6.41 (m, 1H),4.02 (q, 2H, J=6.6 Hz), 1.38 (t, 3H, J=6.9 Hz); ¹⁹F NMR (CD₃OD): -47444; LCMS: ret. time: 21.15 min.; purity: 98%; MS (m/e): 341 (MH⁺).7.3.322N4-(4-Ethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926213) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3,4-ethylenedioxyaniline gaveN4-(4-ethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.87 (d, 1H, J=3Hz), 7.47 (dd, 2H, J=2.4 and 5.1 Hz),7.18 (d, 1H, J=2.4 Hz), 6.91-6.85 (m, 3H), 6.79-6.73 (m, 2H), 6.64 (bs,1H), 4.25 (bs, 4H), 4.05 (q, 2H, J=6.9 Hz), 1.43 (t, 3H, J=7.2 Hz); ¹⁹FNMR (CDCl₃): - 47467; LCMS: ret. time: 24.32 min.; purity: 90%; MS(m/e): 383 (MH⁺). 7.3.323N4-(3,4-Dimethoxyphenyl)-N2-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926145) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with4-ethoxyaniline gaveN4-(3,4-dimethoxyphenyl)-N2-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.90 (bs, 1H), 7.37 (dd, 2H, J=2.4 and 6.3 Hz), 7.21(d, 1H, J=2.4 Hz), 7.03 (dd, 1H, J=2.4 and 8.1 Hz), 6.86-6.80 (m, 4H),6.65 (bs, 1H), 4.00 (q, 2H, J=7.2 Hz), 3.89 (s, 3H), 3.75 (s, 3H), 1.39(t, 3H, J=6.9 Hz); ¹⁹F NMR (CDCl₃): -47501; LCMS: ret. time: 22.69 min.;purity: 98%; MS (m/e): 385 (MH⁺). 7.3.324N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926147) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with3-hydroxyaniline gaveN4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.77 (d, 1H, J=3.3 Hz), 7.15 (d, 1H, J=2.4 Hz), 7.05(dd, 1H, J=2.4 and 8.4 Hz), 7.00-6.90 (m, 4H), 6.80 (d, 1H, J=8.1 Hz),6.40 (m, 1H), 4.05 (q, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.20 (t, 3H);¹⁹F NMR (CD₃OD): - 47223; LCMS: ret. time: 17.94 min.; purity: 99%; MS(m/e): 357 (MH⁺). 7.3.325N2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926113) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3,4-dimethoxyaniline gaveN2-(3,4-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.90 (d, 1H, J=6.6 Hz), 7.59 (bs, 1H), 7.30 (s, 1H),7.20-7.10 (m, 2H), 7.00-6.75 (m, 4H), 6.59 (bd, 1H, J=7.8 Hz), 3.87 (s,3H), 3.84 (s, 3H); ¹⁹F NMR (CDCl₃): - 47229; LCMS: ret. time: 17.77min.; purity: 78%; MS (m/e): 357 (MH⁺). 7.3.326N2-(4-Ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926395) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith ethyl-4-aminophenoxyacetate gaveN2-(4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.90 (d, 1H, J=5.1 Hz), 7.35 (dd, 2H, J=2.1 and 7.2Hz), 7.13 (t, 1H, J=7.2 Hz), 7.10 9d, 1H, J=6.6 Hz), 6.96 (dd, 2H, J=2.4and 7.2 Hz), 6.67 (m, 1H), 4.72 (s, 2H), 4.25 (q, 2H, J=7.2 Hz), 1.29(t, 3H, J=7.2 Hz); ¹⁹F NMR (CD₃OD): - 21885; LCMS: ret. time: 20.18min.; purity: 92%; MS (m/e): 399 (MH⁺). 7.3.3275-Bromo-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926396) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine withethyl 4-aminophenoxyacetate gave5-bromo-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 21.64 min.; purity: 92%; MS (m/e): 459 (MH⁺). 7.3.328N2-(4-Ethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926211) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-ethoxyaniline were reacted to yieldN2-(4-ethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.88 (bs, 1H), 7.40 (bd, 2H, J=8.7 Hz), 7.27 (bd, 2H,J=6.3 Hz), 6.95 (dd, 1H, J=3 and 9 Hz), 6.86-6.77 (m, 3H), 6.58 (s, 1H),4.28 (bs, 4H), 4.01 (q, 2H, J=6.9 Hz), 1.40 (t, 3H, J=6.9 Hz); LCMS:ret. time: 24.46 min.; purity: 90%; MS (m/e): 383 (MH⁺). 7.3.329N2-(3,4-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926212) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,4-dimethoxyaniline were reacted to yieldN2-(3,4-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.98 min.; purity: 74%; MS (m/e): 399 (MH⁺). 7.3.330N2-(3-Chloro-4-fluorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926218) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-chloro-4-fluoroaniline were reacted to yieldN2-(3-chloro-4-fluorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.75 (bd, 1H), 7.70 (bd, 1H), 7.18 (m, 1H), 7.10 (m,1H), 6.90 (m, 2H), 6.75 (m, 1H), 4.20 (bs, 4H); LCMS: ret. time: 25.04min.; purity: 99%; MS (m/e): 392 (MH⁺). 7.3.331N2-(4-tert-Butylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926219) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-tert-butylaniline were reacted to yieldN2-(4-tert-butylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.85 (d, 1H, J=3.6 Hz), 7.44 (bdd, 2H, J=6.3 Hz),7.35-7.31 (m, 3H), 6.93 (dd, 1H, J=2.7 and 8.7 Hz), 6.83 (d, 1H, J=9Hz), 6.80 (bs, 1H), 4.23 (s, 4H), 1.28 (s, 9H); LCMS: ret. time: 27.67min.; purity: 98%; MS (m/e): 395 (MH⁺). 7.3.332N4-(3,4-Ethylenedioxyphenyl)-N2-(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926220) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-fluoroaniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-N2-(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.92 (bs, 1H), 7.80 (bs, 1H), 7.60 (bd, 2H), 6.90 (m,2H), 6.80 (bs, 1H), 6.65 (bs, 1H), 4.25 (s, 4H); LCMS: ret. time: 22.87min.; purity: 97%; MS (m/e): 357 (MH⁺). 7.3.333N4-(3,4-Ethylenedioxyphenyl)-N2-(3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926221) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-fluoroaniline were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-N2-(3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.76 (d, 1H, J=5.6 Hz), 7.39 (m, 2H), 7.14 (d, 1H,J=2.4 Hz), 6.94-6.85 (m, 3H), 6.75 (d, 1H, J=9 Hz), 4.21 (s, 4H); LCMS:ret. time: 22.60 min.; purity: 100%; MS (m/e): 357 (MH⁺). 7.3.334N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxyethyl)-2,4-pyrimidinediamine(R926229) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-methoxyethylamine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)--5-fluoro-N2-(2-methoxyethyl)-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ7.81 (bs,1H), 7.33 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=2.4 Hz and 9 Hz), 6.81 (d,1H, J=9 Hz), 6.53 (s, 1H), 4.25 (bs, 2H), 3.54 (bs, 2H), 3.36 (s, 3H);LCMS: ret. time: 18.01 min.; purity: 100%; MS (m/e): 321 (MH⁺). 7.3.335N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxybenzyl)-2,4-pyrimidinediamine(R926230) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-methoxybenzylamine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxybenzyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.81 (d, 1H, J=2.7 Hz), 7.27 (m, 3H), 6.86 (m, 3H),6.52 (s, 1H). 5.14 (s, 1H), 4.46 (d, 2H, J=5.4 Hz), 4.24 (s, 4H), 3.78(s, 3H); LCMS: ret. time: 23.06 min.; purity: 94%; MS (m/e): 383 (MH⁺).7.3.336N2-(2,2-Difluorobenzodioxol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926386) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2,2-difluoro-5-aminobenzodioxole were reacted to yieldN2-(2,2-difluorobenzodioxol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ9.39 (s, 1H), 9.24 (s, 1H), 8.06 (d, 1H, J=5.6 Hz),7.87 (d, 1H, J=1.8 Hz), 7.27-7.19 (m, 3H), 7.08 (dd, 1H, J=2.4 and 8.7Hz), 6.80 (d, 1H, J=9Hz), 4.21 (bs, 4H); ¹⁹F NMR (CDCl₃): -14012 and -46487; LCMS: ret. time: 25.32 min,; purity:100%; MS (m/e): 419 (MH⁺).7.3.337N2-(2-Ethoxycarbonylindol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926476) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-ethoxycarbonyl-5-aminoindole were reacted to yieldN2-(2-ethoxycarbonylindol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.84 (d, 1H, J=5.4 Hz), 7.76 (d, 1H, J=3.6 Hz), 7.50(d, 1H, J=9 Hz), 7.23-7.15 (m, 3H), 7.03 (bd, 1H, J=8.7 Hz), 6.78 (d,1H, J=8.7 Hz), 4.38 (q, 2H, J=7.2 Hz), 4.22 (s, 4H), 1.41 (t, 3H, J=6.9Hz); LCMS: ret. time: 23.58 min; purity: 100%; MS (m/e): 451 (MH⁺).7.3.338N2-(4-Cyanomethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926480) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-cyanomethyleneoxyaniline were reacted to yieldN2-(4-cyanomethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.87 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=8.7 Hz), 7.38(bs, 1H), 7.28 (d, 1H, J=2.4 Hz), 6.96-6.86 (m, 3H), 6.65 (bd, 1H), 4.73(s, 2H), 4.29 (m, 4H); ¹⁹F NMR (CDCl₃): - 47416; LCMS: ret. time: 20.49min.; purity: 100%; MS (m/e): 394 (MH⁺). 7.3.339N2-(3-Ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926482) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine andethyl-3-aminophenoxyacetate were reacted to yieldN2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ10.53 (s, 1H), 8.18 (s, 1H), 7.67 (d, 1H, J=4.8 Hz),7.19-7.02 (m, 5H), 6.86 (d, 1H, 9Hz), 6.71 (dd, 1H, J=1.8 and 9 Hz),4.51 (s, 2H), 4.25 (m, 6H), 1.29 (t, 3H, J=7.5 Hz); ¹⁹F NMR (CDCl₃): -45640; LCMS: ret. time: 22.71 min.; purity: 99%; MS (m/e): 441 (MH⁺).7.3.340N2-(3-Ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925745) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-ethoxycarbonylaniline gaveN2-(3-ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.04 (bs, 1H), 7.94 (bs, 1H), 7.90 (bd, 1H), 7.68 (bd,1H, J=7.5 Hz), 7.35 (t, 1H, J=8.1 Hz), 7.28 (d, 1H, J=2.4 Hz), 7.07 (s,1H), 6.93 (dd, 1H, J=3 and 8.7 Hz), 6.83 (d, 1H, J=9 Hz), 6.64 (bs, 1H),4.36 (q, 2H, J=7.2 Hz), 4.26 9s, 4H), 1.35 (t, 3H, J=7.5 Hz); ¹⁹F NMR(CDCl₃): - 47247; LCMS: ret. time: 15.88.; purity: 100%; MS (m/e): 411(MH⁺). 7.3.341N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine(R925746) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamineand2-hydroxyethylamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.7 (bs, 1H), 7.32 (d, 1H, J=2.4 Hz), 7.05 (dd, 1H,J=2.4 and 9 Hz), 6.75 (d, 1H, J=8.9 Hz), 4.21 (s, 4H), 3.67 (t, 2H,J=5.7 Hz), 3.38 (t, 2H, J=5.4 Hz); ¹⁹F NMR (CD₃OD): - 48518; LCMD: ret.time: 15.54 min.; purity: 100%; MS (m/e): 307 (MH⁺). 7.3.342N2-(4-Ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925747) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamineandethyl-4-aminophenoxyacetate gaveN2-(4-oxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.88 (bs, 1H), 7.42 (dd, 2H, J=2.4 and 6.9 Hz), 7.28(d, 1H, J=3 Hz), 6.95-6.81 (m, 4H), 6.59 (s, 1H), 4.59 (s, 4H), 4.28 (q,2H, J=6.2 Hz), 1.30 (t, 3H, J=6.1 Hz); ¹⁹F NMR (CDCl3): - 47570; LCMS:ret. time: 22.74 min.; purity: 100%; MS (m/e): 441 (MH⁺). 7.3.343N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940233) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-chloro-4-hydroxy-5-methylaniline gaveN2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: retn, time: 19.20 min.; purity: 94%; MS (m/e): 360 (M⁺); ¹H NMR(CDCl₃): δ7.93 (1H, d, J=3.1 Hz), 7.54 (1H, d, J=2.6 Hz), 7.30 (1H, t,J=2.1 Hz), 7.21 (1H, t, J=7.9 Hz), 7.02 (3H, m), 6.78 (1H, s), 6.61 (1H,dd, J=7.9 Hz, J=2.1 Hz), 2.26 (3H, s). 7.3.344N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940235) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-4-pyrimidineaminewith 3-hydroxyaniline gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: retn, time: 18.20 min.; purity: 94%; MS (m/e): 360 (M⁺); 1H NMP(DMSO-d₆): δ9.26 (1H, s), 9.23 (1H, s), 9.16 (1H, s), 8.89 (1H, s), 8.14(1H, d, J=4.5 Hz), 7.66 (1H, d, J=2.1 Hz), 7.60 (1H, d, J=2.1 Hz), 7.29(1H, d, J=8.4 Hz), 7.11 (1H, s), 7.06 (1H, t, J=8.4 Hz), 6.41 (1H, d,J=8.4 Hz), 2.30 (3H, s). 7.3.345N2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine(R940250) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-4-pyrimidineaminewith 3,4-dimethoxyaniline gaveN2-(3,4-dimethoxyphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine.LCMS: retn, time: 14.72 min.; purity: 94%; MS (m/e): 484 (MH⁺); ¹H NMR(CDCl₃): δ7.89 (1H, d, J=3.3 Hz), 7.47 (2H, d, J=9 Hz), 7.22 (1H, d,J=2.2 Hz), 6.93-6.76 (5H, m), 6.64 (1H, d, J=2.2 Hz), 4.01 (2H, t, J=5.6Hz), 3.86 (3H, s), 3.72 (3H, s), 3.71 (4H, m), 2.58-2.44 (6H, m), 1.97(2H, m). 7.3.346 N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine(R940251) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-4-pyrimidineaminewith 2-chloro-4-hydroxy-5-methylaniline gaveN2-(2-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine.LCMS: retn, time: 15.19 min.; purity: 94%; MS (m/e): 488 (MH⁺); ¹H NMR(CDCl₃): δ7.89 (1H, d, J=3.3 Hz), 7.52 (1H, d, J=2.5 Hz), 7.44 (2H, d,8.7 Hz), 6.97 (1H, d, J=2.5 Hz), 6.91 (2H, d, 9 Hz), 6.71 (1H, s), 6.64(1H, 2.5 Hz), 4.03 (2H, t, J=6.03 Hz), 3.74 (4H, t, J=4.65 Hz),2.60-2.43 (6H, m), 2.23 (3H, s), 1.49 (2H, m). 7.3.347N4-(3,5-Dimethyl-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940253) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineaminewith ethyl 3-aminophenoxyacetate gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: retn, time: 21.79 min.; purity: 91 %; MS (m/e): 427 (MH⁺); 1H NMR(DMSO-d₆): δ9.80 (1H, s), 8.30 (1H, s), 8.23 (1H, d, J=4.5 Hz),7.37-7.17 (5H, m), 6.66 (1H, d, J=9 Hz), 4.73 (2H, s), 4.25 (2H, q,J=7.2 Hz), 2.23 (6H, s), 1.29 (3H, t, J=7.0 Hz). 7.3.348N2-(3-tert-Butylphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinediamine(R940266) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3-tert-butylaniline gaveN2-(3-tert-butylphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinediamine.LCMS: retn, time: 28.17 min.; purity: 96 %; MS (m/e): 439 (M⁺), 440(MH⁺); ¹H NMR (DMSO-d₆): δ9.40 (1H, s), 9.19 (1H, s), 8.21 (1H, d, J=3.6Hz), 7.78 (1H, d, J=8.5 Hz) 7.60 (2H, m), 7.48 (1H, t, J=2 Hz), 7.31(1H, t, J=8.5 Hz), 7.25 (1H, t, J=8.5 Hz), 7.02 (1H, d, J=8.5 Hz), 6.70(1H, dd, J=8.5 and 2 Hz), 4.79 (2H, s), 4.26 (2H, q, J=7.2 Hz), 1.33(9H, s), 1.29 (3H, t, J=7.2 Hz). 7.3.3495-Fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineand 5-fluoro-N2-(2-ethoxoxycarbonylbenzofur-5-yl)-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine R940284 In like manner to thepreparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-isopropylphenyl)-4-pyrimidineamine and ethyl3-aminophenoxyacetate were reacted to give the mixture of5-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineand 5-fluoro-N2-(2-ethoxoxycarbonylbenzofur-5-yl)-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine. (R =CO₂Me). LCMS: retn,time: 25.41 min.; purity: 60.61 %; MS (m/e): 411 (MH⁺); 1H NMR(DMSO-d₆): δ9.38 (1H, s), 9.29 (1H, s), 8.20 (1H, d, J=3.9 Hz), 7.85(1H, d, J=9.3 Hz), 7.58 (1H, t, J=1.6 Hz), 7.43-7.33 (3H, m), 7.18 (1H,t, J=8.2 Hz), 7.05 (1H, d, J=7.8 Hz), 6.53 (1H, dd, J=8.4 Hz, J=2.1 Hz),4.72 (2H, s), 3.79 (3H, s), 2.95 (1H, quint, J=7.2 Hz), 1.26 (6H, d,J=7.2 Hz) (R =CO₂Et) LCMS: retn, time: 26.99 min.; purity: 39 %; MS(m/e): 425 (MH⁺); 1H NMR (DMSO-d₆): δ9.38 (1H, s), 9.29 (1H, s), 8.20(1H, d, J=3.9 Hz), 7.85 (1H, d, J=9.3 Hz), 7.58 (1H, t, J=1.6 Hz),7.43-7.33 (3H, m), 7.18 (1H, t, J=8.2 Hz), 7.05 (1H, d, J=7.8 Hz), 6.53(1H, dd, J=8.4 and 2.1 Hz), 4.71 (2H, s), 4.25 (2H, q, J=7.2 Hz), 2.95(1H, quint, J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz), 1.26 (6H, d, J=7.2 Hz).7.3.350N4-(3-tert-Butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940281 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine and2-methoxycarbonyl-5-aminobenzofuran were reacted to giveN4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine.LCMS: retn, time: 26.76 min.; purity: 97 %; MS (m/e): 435 (MH⁺); 1H NMR(DMSO-d₆): δ9.41 (2H, sl), 8.27 (1H, s), 8.21 (1H, d, J 3.9 Hz), 7.98(1H, m), 7.77-7.60 (3H, m), 7.37 (1H, t, J 8.1 Hz), 7.22 (1H, d, J 8.1Hz), 3.98 (3H, s), 1.34 (9H, s). 7.3.3515-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940283 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-isopropylphenyl)-4-pyrimidineamine and2-methoxycarbonyl-5-aminobenzofuran were reacted to give5-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine.LCMS: retn, time: 26.05 min.; purity: 99 %; MS (m/e): 420 (M⁺), 422(MH⁺); ¹H NMR (DMSO-d₆): δ10.00 (1H, s), 9.95 (1H, s), 8.31 (1H, d,J=4.8 Hz), 8.11 (1H, s), 7.74 (3H, m), 7.35 (1H, s), 7.35 (1H, t, J=7.2Hz), 7.12 (1H, d, J=7.2 Hz), 3.99 (3H, s), 2.83 (1H, sept, J=6.9 Hz),1.20 (6H, d, J=6.9 Hz). 7.3.352N2-(1,1-Dihydroisobenzofuran-1-one-6-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926786) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with6-amino-1,1-dihydroisobenzofuran-1-one gaveN2-(1,1-dihydroisobenzofuran-1-one-6-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.20 (s, 1H), 9.85 (s, 1H), 8.22 (d, 1H, J=4.8 Hz),8.10 (d, 1H, J=1.2 Hz), 7.86 (dd, 1H, J=2.4 and 8.7 Hz), 7.54 (d, 1H,J=8.4 Hz), 7.22 (d, 1H, J=2.4 Hz), 7.13 (dd, 1H, J=2.1 and 9 Hz), 6.81(d, 1H, J=8.7 Hz), 5.34 (s, 2H), 4.20 (s, 4H); LCMS: ret. time: 17.40min.; purity: 83%; MS (m/e): 395 (MH⁺). 7.3.353N2-[3-(3-Acetamidophenoxy)propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926787) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-N-acetamidophenoxy-3-propylamine gaveN2-[3-(3-acetamidophenoxy)propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.45 (bs, 1H), 10.07 (s, 1H), 8.42 (s, 1H), 8.20 (s,1H), 7.37 (d, 1H, J=3 Hz), 7.31 (s, 1H), 7.20-7.05 (m, 3H), 6.83 (d, 1H,J=9Hz), 6.53 (d, 1H, J=6.6 Hz), 4.18 (s, 4H), 3.95 (t, 2H, J=6 Hz), 2.48(m, 2H), 2.07 (s, 3H), 1.96 (t, 3H, J=7.8 Hz); LCMS: ret. time: 19.58min.; purity: 99%; MS (m/e): 454 (MH⁺). 7.3.354N2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926788) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with4,5-dichloro-1H-imidazoleamine gaveN2-[4-(4,5-dichloro-1H-imidazol-1-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.10 (s, 1H), 9.85 (s, 1H), 8.20 (d, 1H, J=4.2 Hz),8.01 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.36 (d, 1H, J=9 Hz), 7.25 (d, 1H,J=3 Hz), 7.14 (dd, 1H, J=2.1 and 9 Hz), 6.85 (d, 1H, J=8.7 Hz); LCMS:ret. time: 23.59 min.; purity: 95%; MS (m/e): 474 (MH⁺). 7.3.355N2-(2,4-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926789) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with2,4-dimethoxyaniline gaveN2-(2,4-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.35 (s, 1H), 8.14 (bd, 1H), 7.38 (d, 1H, J=9 Hz),7.23 (s, 1H), 7.09 (d, 1H, J=8.7 Hz), 6.79 (d, 1H, J=8.7 Hz), 6.66 (d,1H, J=2.4 Hz), 6.49 (dd, 1H, J=2.4 and 9 Hz), 4.22 (s, 4H), 3.77 (s,6H); LCMS: ret. time: 20.93 min.; purity: 98%; MS (m/e): 399 (MH⁺).7.3.356N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine(R926790) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with4-isopropylaniline gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.30 (s, 1H), 10.50 (s, 1H), 8.22 (d, 1H, J=5.4 Hz).7.37 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=3 Hz), 7.18 (s, 1H), 7.15 (s,1H), 7.06 (dd, 1H, J=3.3 and 8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 4.23 (s,4H), 2.85 (sept., 1H, J=7.2 Hz), 1.17 (d, 6H, J=6.9 Hz); LCMS: ret.time: 24.91 min.; purity: 95%; MS (m/e): 381 (MH⁺). 7.3.357N2-(3,5-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926791) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3,4-dimethoxyaniline gaveN2-(3,5-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.08 (s, 1H), 9.99 (s, 1H), 8.19 (m, 1H), 7.21 (d,1H, J=2.4 Hz), 7.14 (dd, 1H, J=2.1 and 8.7 Hz), 6.79 (d, 1H, J=9 Hz),6.72 (s, 1H), 6.20 (d, 1H, J=1.8 Hz), 4.21 (s, 4H); LCMS: ret. time:21.19 min.; purity: 93%; MS (m/e): 399 (MH⁺). 7.3.358N2-(2,5-Dimethyl-4-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926792) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with2,5-dimethyl-4-hydroxyaniline gaveN2-(2,5-dimethyl-4-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.69 (d, 1H, J=3.9 Hz), 7.16 (d, 1H, J=2.4 Hz), 7.05(d, 1H, J=2.4 Hz), 7.02 (d, 1H, J=1.2 Hz), 6.66 (s, 1H), 6.63 (s, 1H),6.62 (s, 1H), 4.19 (s, 4H), 2.12 (s, 3H), 2.10 (s, 3H); LCMS: ret. time:19.80 min.; purity: 90%; MS (m/e): 383 (MH⁺). 7.3.359N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine(R926793) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with5-methyl-3-phenyl-4-oxazolylamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.80-7.65 (m, 2H), 7.45 (bd, 1H), 7.20 (m, 1H), 7.00(m, 1H), 6.65 (bd, 1H), 4.20 (s, 4H), 2.35 (s, 3H); LCMS: ret. time:20.61 min.; purity: 78%; MS (m/e): 420 (MH⁺). 7.3.360N4-(3,5-Dimethoxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926795) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine withethyl-3-aminophenoxyacetate gaveN4-(3,5-dimethoxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 21.02 min.; purity: 84%; MS (m/e): 429 (MH⁺). 7.3.361N4-(3,4-Ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926797) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dimethoxyphenyl)-5-ethoxycarbonyl-4-pyrimidineaminewith ethyl-3-aminophenoxyacetate gaveN4-(3,4-ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.LCMS: ret. time: 27.60 min.; purity: 82%; MS (m/e): 495 (MH⁺). 7.3.362N4-(3-Hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926798) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro--5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-4-pyrimidineamine withethyl-3-aminophenoxyacetate gaveN4-(3-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.LCMS: ret. time: 24.78 min.; purity: 85%; MS (m/e): 453 (MH⁺). 7.3.3635-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R926614) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 2-methoxycarbonyl-5-aminobenzofuran gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ9.42 (s, 1H), 9.33 (s, 1H), 9.23 (s, 1H), 8.26 (s, 1H),8.09 (d, 1H, J=3.6 Hz), 7.59 (m, 3H), 7.13 (m, 3H), 6.53 (d, 1H, J=7.5Hz), 3.87 (s, 3H), 3.87 (s, 3H). 7.3.364N2-(2-Ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926615) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 2-ethoxycarbony-5-aminoindole gaveN2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.95 (d, 1H), 7.84 (d, 1H, J=3.9 Hz), 7.34 (s, 1H),7.33 (d, 1H, J=1.8 Hz), 7.22-7.19 (m, 2H), 7.11-7.05 (m, 2H), 6.55 (m,1H), 4.62 (s, 2H), 4.38 (q, 1H, J=6.9 Hz), 1.40 9t, 3H, J=7.5 Hz).7.3.365N2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926777) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith (4,5-dichloro-1H-imidazol-1-yl)-4-aniline gaveN2-[4-(4,5-dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 22.09 min.; purity: 98%; MS (m/e): 431 (MH⁺). 7.3.3665-Fluoro-N4-(3-hydroxyphenyl)-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine(R926778) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 4-isopropylaniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.08 min.; purity: 99%; MS (m/e): 439 (MH⁺). 7.3.3675-FluoroN4-(3-hydroxyphenyl)-N2-(5-methyl-4-oxazolyl-2-phenyl)-2,4-pyrimidinediamine(R926779) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 5-methyl-4-oxazolyl-2-phenyl-1-amine gave 5-fluoroN4-(3-hydroxyphenyl)-N2-(5-methyl-4-oxazolylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.08 min.; purity: 99%; MS (m/e): 439 (MH⁺). LCMS:ret. time: 19.17 min.; purity: 81%; MS (m/e): 378 (MH⁺). 7.3.368N2-(3.5-Dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926780) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3.5-dimethoxyaniline gaveN2-(3.5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.61 min.; purity: 97%; MS (m/e): 357 (MH⁺). 7.3.369N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl-2,4-pyrimidinediamine(R926572) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineaminewith methyl 4-aminophenoxyacetate gaveN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.49 (d, 2H, J=8.7 Hz), 7.40 (d, 2H, J=9.3 Hz), 6.89(d, 2H, J=9.3 Hz), 6.85 (d, 2H, J=8.7 Hz), 4.62 (s, 2H), 4.52 (s, 2H),3.81 (s, 3H), 1.49 (s, 9H); LCMS: ret. time: 24.68 min.; purity: 100%;MS (m/e): 499 (MH⁺). 7.3.3705-Fluoro-N4-(3-isopropoxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R926487) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3-isopropoxyphenyl)-4-pyrimidinediamineamine with2-methoxycarbonyl-5-aminobenzofuran gave5-fluoro-N4-(3-isopropoxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.09 (d, 1H, J=2.4 Hz), 7.96 (d, 1H, J=3 Hz), 7.52 (s,1H), 7.48 (t, 1H, J=1.8 Hz), 7.40 (dd, 1H, J=6.3 Hz), 7.24 9m, 2H), 7.10(m, 1H), 6.97 (bs, 1H), 6.74 (d, 1H, J=2.4 Hz), 6.68 (dd, 1H, J=2.1 and6.9 Hz), 4.49 (sept., 1H, J=5.7 Hz), 3.98 (s, 3H), 1.30 (d, 6H, J=5.7Hz); LCMS: ret. time: 25.86 min.; purity: 94%; MS (m/e): 437 (MH⁺).7.3.371N4-(4-tert-Butylphenyl)-N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine(R926474) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(tert-butylcarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineaminewith 2-ethoxycarbony-5-aminolindole gaveN4-(4-tert-butylphenyl)-N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.05 (d, 1H, J=1.8 Hz), 7.85 (d, 1H, J=3.9 Hz), 7.58(d, 2H, J=9 Hz), 7.36-7.10 (m, 4H), 7.03 (s, 1H), 6.95 (bd, 1H), 6.84(dd, 1H, J=7.2 Hz), 4.36 (q, 2H, J=7.2 Hz), 1.40 (t, 3H, J=7.5 Hz), 1.33(s, 9H); LCMS: ret. time: 28.67 min.; purity: 100%; MS (m/e): 449 (MH⁺).7.3.372N4-(4-tert-Butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R926477) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(tert-butylcarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineaminewith 2-methoxycarbonyl-5-aminobenzofuran gaveN4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.6 (s, 1H), 8.09 )d, 1H, J=1.8 Hz), 7.86 (d, 1H, J=3.3Hz), 7.54-7.36 (m, 6H), 6.90 (m, 1H)3.97 (s, 3H), 1.36 (s, 9H), ¹⁹F NMR(CDCl₃): - 47188; LCMS: ret. time: 29.69 min.; purity: 84%; MS (m/e):393 (M-41). 7.3.373N2-(3,4-Ethylenedioxyphenyl)-N4-(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R926485) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine with2-methoxycarbonyl-5-aminobenzofuran gaveN2-(3,4-ethylenedioxyphenyl)-N4-(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.07 (s, 1H), 7.76 (s, 1H), 7.44 (m, 3H), 7.13 (m, 1H),6.68 (m, 2H0, 4.18 (s, 4H), 3.95 (s, 3H); LCMS: ret. time: 26.63 min.;purity:100%; MS (m/e): 437 (MH⁺). 7.3.374N4-(3-Ethoxycarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926774) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidineaminewith 3,4-ethylenedioxyaniline gaveN4-(3-ethoxycarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.92 (d, 1H, J=3.6 Hz), 7.67 (s, 1H), 7.40 (s, 1H),7.28-7.21 (m, 2H), 7.01-6.96 (m, 2H), 6.80 (m, 2H), 6.68 (bd, 1H, 1H),4.61 (s, 2H), 4.25 (m, 6H), 1.25 (t, 3H, J=6.9 Hz); LCMS: ret. time:22.03 min.; purity: 84%; MS (m/e): 441 (MH⁺). 7.3.375N4-(3-Ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926775) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidineaminewith 3-hydroxyaniline gaveN4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.50 min.; purity: 84%; MS (m/e): 399 (MH⁺). 7.3.376N4-(4-Aminocarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945171) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineamineand 3,4-ethylenedioxyaniline gaveN4-(4-aminocarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δδ4.24-4.31 (m, 4H), 4.51 (s, 2H), 6.77 (d, J=8.7Hz, 1H), 6.95 (dm, J=8.7 Hz, 1H), 7.06 (d, J=9.3 Hz, 2H), 7.28 (m, 1H),7.71 (d, J=9.0 Hz, 2H), 8.15 (m, 1H); LCMS: 15.23 min, 97.05%; MS (m/e):412.01 (MH⁺). 7.3.377 (R935019):5-Fluoro-N2-(3-hydroxyphenyl)-N4-[di-(4-chlorophenyl)methyl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine,3-aminophenol andN-(2-chloro-5-fluoro-pyrimidinyl)-1,1-di(4-chlorophenyl)methylamineproduced5-fluoro-N2-(3-hydroxyphenyl)-N4-[di-(4-chlorophenyl)methyl]-2,4-pyrimidinediamine.LCMS: ret. time: 25.59 min.; purity: 91%; MS (m/e): 421 (MH⁺-Cl).7.3.378 (R935020):N4-(Fluoren-9-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine:In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine,2-chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine and 3-aminophenolwere reacted to produceN4-(fluoren-9-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.85 (d, 1H, J=2.9 Hz), 7.74 (d, 2H, J=7.6 Hz), 7.64(d, 2H, J=7.6 Hz), 7.41-7.28 (m, 6H), 7.14-7.05 (m, 2H), 6.56 (d, 1H,J=8.8 Hz), 5.28 (d, 1H, J=8.8 Hz); LCMS: ret. time: 23.27 min.; purity:89%; MS (m/e): 385 (MH⁺). 7.3.379 (R935021):(±)-5-Fluoro-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and(±)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine werereacted to produce the desired (±)-5-fluoro-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ7.79 (d, 1H, J=3.3 Hz), 7.38-7.34(dd, 2H, J=5.2 and 8.5 Hz), 7.14 (t, 1H, J=4.5 Hz), 7.09 (d, 1H, J=8.5Hz), 7.03 (d, 1H, J=8.5 Hz), 6.84 (br s, 1H), 6.84-6.78 (ddd, 1H, J=0.8,2.0, and 8.2 Hz), 6.46-6.42 (ddd, 1H, J=0.8, 2.0 and 8.2 Hz), 5.26(overlapped dq, 1H, J=7.1 and 7.9 Hz), 5.18 (d, 1H, J=7.1 Hz), 1.59 (d,3H, J=7.1 Hz); LCMS: ret. time: 21.52 min.; purity: 92%; MS (m/e): 343(MH⁺). 7.3.380 (R935023):(±)-5-Bromo-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and(±)-5-bromo-2-chloro-N4-[1-(4-fluorophenyl)ethyl]-4-pyrimidineamine werereacted to produce (±)-5-bromo-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.97 (s, 1H), 7.36-7.31 (m, 2H), 7.17 (s, 1H),7.09-7.01 (m, 4H), 6.82 (dd, 1H, J=2.2 and 8.2 Hz), 6.46 (d, 1H, J=2.2and 8.2 Hz), 5.50 (br d, 1H, J=7.0), 5.27 (overlapped dq, 1H, J=7.1 and7.9 Hz), 1.58 (d, 3H, J=7.0 Hz); LCMS: ret. time: 22.64 min.; purity:94%; MS (m/e): 404 (MH⁺) 7.3.381 (R935025):5-Bromo-N2-(3-hydroxyphenyl)-N4-(N-methyl-2-carbomethoxypyrrol-4-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and5-bromo-2-chloro-N-(N-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidineaminewere reacted to give5-bromo-N2-(3-hydroxyphenyl)-N4-(N-methyl-5-carbomethoxypyrrol-4-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃ + CD₃OD): δ7.92 (s, 1H), 7.58 (d, 1H, J=8.0 Hz), 7.09 (d,1H, J=8.5 Hz), 7.04 (d, 1H, J=8.5 Hz), 6.90 (d, 1H, J=4.5 Hz), 6.81 (d,1H, J=1.8 Hz), 6.5 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H): LCMS: ret. time:19.73 min.; purity: 90%; MS (m/e): 419 (MH⁺) 7.3.382 (R935029):4-Amino-5-bromo-N2-(3-hydroxyphenyl)-2-pyrimidineamine In like manner tothe preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine,4-amino-5-bromo-2-chloropyrimidine and 3-aminophenol were reacted togive 4-amino-5-bromo-N2-(3-hydroxyphenyl)-2-pyrimidineamine. ¹H NMR(DMSO-d₆): δ10.33 (br s, 1H), 8.27 (s, 1H), 7.14-6.06 (m, 2H), 7.01 (d,1H, J=1.7 Hz), 6.54 (td, 1H, J=1.7 Hz and 7.0 Hz). 7.3.383 R935134:5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineThe reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamineand 5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted inmicrowave at 180° C. for 10-20 minutes at 20 bar. Upon concentration andaddition of 2N HCl provided5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.21 (br s, 1H), 9.91 (br s, 1H), 8.18 (d, 1H, J=5.2Hz), 8.03-7.99 (m, 2H), 7.61-7.53 (m, 3H), 7.46 (br d, 2H, J=7.9 Hz),7.14-7.01 (m, 5H), 6.54 (app d, 1H, J=7.96 Hz), 5.56 (s, 2H); LCMS: ret.time: 24.61 min.; purity: 100%; MS (m/e): 471 (MH⁺). 7.3.384 R935135:5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted toprovide 5-fluoro-N4-(4-isopropyloxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d₆): δ10.21 (br s, 1H), 9.93(br s, 1H), 8.17 (d, 1H, J=5.2 Hz), 8.02-7.98 (m, 2H), 7.60-7.49 (m,5H), 7.42 (app d, 2H, J=7.0 Hz), 7.04 (d, 2H, J=9.4 Hz), 6.89 (app d,2H, J=9.4 Hz), 5.56 (s, 2H), 4.58 (septet, 1H, J=6.4 Hz), 1.23 (app d,6H, J=6.4 Hz); LCMS: ret. time: 26.90 min.; purity: 97%; MS (m/e): 513(MH⁺). 7.3.385 R935136:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxy)phenyl-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d₆): δ10.18 (br s, 1H), 9.12(br s, 1H), 8.14 (d, 1H, 4.7 Hz), 8.02-7.97 (m, 2H), 7.65-7.52 (m, 3H),7.44 (d, 2H, J=8.8 Hz), 7.25-7.23 (m, 1H), 7.15-7.08 (m, 1H), 7.03 (d,2H, J=8.8 Hz), 6.81 (d, 1H, J=8.8 Hz), 5.56 (s, 2H), 4.24-4.20 (m, 4H);LCMS: ret. time: 26.90 min.; purity: 97%; MS (m/e): 513 (MH⁺). 7.3.386R935137:5-Fluoro-N4-(2-methoxycarbonylbenzofura-5-yl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-methoxycarbonylbenzofura-5-yl)-4-pyrimidineamineand 5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole were reacted toprovide5-fluoro-N4-(2-methoxycarbonylbenzofura-5-yl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.21 (br s, 1H), 9.79 (br s, 1H), 8.19 (d, 1H, J=4.7Hz), 8.09 (br s, 1H), 7.99 (dd, 2H, J=2.3 and 8.2 Hz), 7.76-7.67 (m,2H), 7.59-7.52 (m, 4H), 7.44 (d, 2H, J=8.8 Hz), 7.02 (d, 2H, J=8.8 Hz),5.55 (s, 2H), 3.85 (s, 3H); LCMS: ret. time: 27.61 min.; purity: 92%; MS(m/e): 553 (MH⁺). 7.3.387 R935138:5-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3-aminophenol were reacted to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d₆): δ8.12 (d, 1H, J=4.7 Hz),8.03-7.99 (m, 2H), 7.69 (dd, 2H, J=3.5 and 8.8 Hz), 7.61-7.53 (m, 3H),7.06 (d, 2H, J=9.9 Hz), 6.98 (m, 3H), 6.38 (br s, 1H), 5.58 (s, 2H).LCMS: ret. time: 24.83 min.; purity: 96%; MS (m/e): 471 (MH⁺). 7.3.388R935139:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 4-isopropoxyaniline were reacted to provide 5-fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d₆): δ10.21 (br s, 1H), 9.78(br s, 1H), 8.13 (d, 1H, J=4.7Hz), 8.02-7.98 (m 2H), 7.65-7.53 (m, 5H),7.34 (d, 2H, J=7.6 Hz), 7.07 (d, 2H, J=9.3 Hz), 6.86 (d, 2H, J=8.8 Hz),5.59 (s, 2H), 4.54 (sept, 1H, J=5.8 Hz), 1.22 (d, 6H, J=5.8 Hz); LCMS:ret. time: 29.64 min.; purity: 97%; MS (m/e): 513 (MH⁺). 7.3.389R935140:N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to provideN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.31 (br s, 1H), 9.59 (br s, 1H), 8.11 (d, 1H, J=4.7Hz), 8.03-7.99 (m, 2H), 7.68-7.49 (m, 5H), 7.14-7.08 (m, 1H), 7.06 (d,2H, J=8.8 Hz), 6.90 (d, 1H, J=8.8 Hz), 6.76 (d, 1H, J=8.8 Hz), 5.59 (s,2H), 4.22-4.17 (m, 4H); LCMS: ret. time: 21.35 min.; purity: 95%; MS(m/e): 513 (MH⁺). 7.3.390 R935141:5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine:In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole were reacted toprovide5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d₆): δ10.91 (br s, 1H), 9.91(br s, 1H), 8.18 (d, 1H, J=4.7 Hz), 7.43 (d, 2H, J=8.8 Hz), 7.15-7.04(m, 3H), 6.96 (d, 2H, J=8.8 Hz), 6.58 (app d, 1H, J=7.6 Hz), 5.43 (s,2H), 2.34 (s, 3H); LCMS: ret. time: 18.68 min.; purity: 95%; MS (m/e):409 (MH⁺). 7.3.391 R935142:5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole were reacted toprovide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d₆): δ8.16 (d, 1H, J=5.2 Hz),7.52 (dd, 2H, J=3.5 Hz and 9.3 Hz), 7.40 (d, 2H, J=8.8 Hz), 6.98 (d, 2H,J=8.8 Hz), 6.88 (d, 2H, J=9.3 Hz), 5.44 (s, 2H), 4.58 (sept, 1H, J=5.8Hz), 2.34 (s, 3H), 1.24 (d, 6H, J=5.8 Hz); LCMS: ret. time: 24.47 min.;purity: 93%; MS (m/e): 451 (MH⁺). 7.3.392 R935143:N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxy)phenyl-4-pyrimidineamine and5-(4-aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole were reacted toprovideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d₆): δ9.12 (br s, 1H), 9.04(br s, 1H), 7.99 (d, 1H, J=3.5 Hz), 7.55 (d, 2H, J=1.7 and 8.8 Hz), 7.30(d, 1H, J=2.9 Hz), 7.17 (td, 1H, J=2.9 and 8.8 Hz), 6.88 (d, 2H, J=8.8Hz), 6.77 (d, 1H, J=8.8 Hz), 5.38 (s, 2H), 4.24-4.20 (m, 4H), 2.34 (s,3H); LCMS: ret. time: 21.34 min.; purity: 97%; MS (m/e): 451 (MH⁺).7.3.393 R935144:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 4-isopropoxyaniline were reacted to provide 5-fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the solid. ¹H NMR (DMSO-d₆): δ10.11 (br s, 1H), 9.72(br s, 1H), 8.12 (s, 1H, J=5.3 Hz), 7.61 (dd, 2H, J=8.8 Hz), 7.34 (d,2H, J=7.3 Hz), 7.01 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 5.47 (s,2H), 4.54 (septet, 1H, J=5.8 Hz), 2.34 (s, 3H), 1.23 (d, 6H, J=6.4 Hz);LCMS: ret. time: 24.31 min.; purity: 96%; MS (m/e): 451 (MH⁺). 7.3.394R935145:N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to provideN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.81 (br s, 1H), 9.67 (br s, 1H), 8.13 (d, 1H, J=4.7Hz), 7.63 (dd, 2H, J=4.1 and 8.8 Hz), 7.07 (m, 1H), 7.00 (d, 2H, J=8.8Hz), 6.89 (d, 1H, J=8.8 Hz), 6.76 (d, 1H, J=8.8 Hz), 5.46 (s, 2H),4.22-4-18 (m, 4H), 2.34 (s, 3H); LCMS: ret. time: 21.54 min.; purity:97%; MS (m/e): 451 (MH⁺). 7.3.395 R935146:5-Fluoro-N2-(2-methoxycarbonylbenzofura-5-yl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 2-methoxycarbonyl-5-aminobenzofuran were reacted to provide5-fluoro-N2-(2-methoxycarbonylbenzofura-5-yl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.14 (d, 1H, J=4.7 Hz), 8.02 (s, 1H), 7.63-7.56 (m,5H), 7.02 (d, 2H, J=8.8 Hz), 5.47 (s, 2H), 3.85 (s, 3H), 2.34 (s, 3H);LCMS: ret. time: 22.46 min.; purity: 97%; MS (m/e): 491 (MH⁺). 7.3.396R935147:5-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3-hydroxyaniline were reacted to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas fine flakes of the product. ¹H NMR (DMSO-d₆): δ8.11 (d, 1H, J=4.6Hz), 7.66 (d, 2H, J=5.8 Hz), 7.06-6.97 (m, 5H), 6.42-40 (m, 1H), 5.46(s, 2H), 2.35 (s, 3H); LCMS: ret. time: 19.00 min.; purity: 95%; MS(m/e): 409 (MH⁺). 7.3.397 R935148:N2-(3,4-Ethylenedioxyphenyl)-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-Chloro--[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-2,4-pyrimidine amine and 3,4-ethylenedioxyaniline were reacted to produeN2-(3,4-ethylenedioxyphenyl)-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J=3.5 Hz),7.70 (d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=2.3 Hz), 7.23 (d, 2H, J=8.8 Hz),6.98 (dd,, 1H, J=2.1 and 8.8 Hz), 6.66 (d, 1H, 8.2 Hz); 4.19-4.15 (m,4H), 4.07 (qt, 2H, J=7.0 Hz), 1.48 (s, 6H), 1.10 (t, 3H, J=7.0 Hz);LCMS: ret. time: 24.51 min.; purity: 100%; MS (m/e): 453 (MH⁺). 7.3.398R935150:N2-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(or it can be be prepared similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine),2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and4-[ethoxycarbonyl(dimethyl)methyl]aniline were reacted to produceN2-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.18 (br s, 1H), 9.11 (br s, 1H), 8.01 (d, 1H, J=3.5Hz), 7.56 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=8.8 Hz), 7.09 (d, 2H, J=8.8Hz), 6.86 (d, 2H, J=8.8 Hz), 4.56 (sept, 1H, J=5.8 Hz), 4.02 (qt, 2H,J=7.0 Hz), 1.43 (s, 6H), 1.26 (d, 6H, J=7.0 Hz), 1.09 (t, 3H, J=7.0 Hz);LCMS: ret. time: 28.49 min.; purity: 98%; MS (m/e): 453 (MH⁺). 7.3.399R935179: N2-[4-(2,3-Dihydroxypropoxy)phenyl]-N4-(3,4-ethylenedioxypheny)-5-fluoro-2,4-pyrimidinediamine In likemanner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine and4-(2,3-dihydroxypropoxy)aniline were reacted to produceN2-[4-(2,3-dihydroxypropoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.09 (s, 1H), 8.95 (s, 1H), 7.98 (d, 1H, J=3.5 Hz),7.51 (d, 2H, J=8.8 Hz), 7.32 (d, 1H, J=2.3 Hz), 7.17 (dd, 1H, J=2.3 and8.8 Hz), 6.77 (dd, 3H, J=8.8 Hz), 4.90 (d, 1H, J=5.3 Hz), 4.64 (t, 1H,J=5.8 Hz), 4.23-4.19 (m, 4H), 3.91-3.89 (m, 1H), 3.80-3.73 (m, 2H), 3.41(t, 2H, J=5.3 Hz); LCMS: ret. time: 15.04 min.; purity: 96%; MS (m/e):429 (MH⁺). 7.3.400 R935180:N2-[4-(2,3-Dihydroxypropoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine and4-(2,3-dihydroxypropoxy)aniline were reacted to produceN2-[4-(2,3-dihydroxypropoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.38 (s, 1H), 9.18 (s, 1H), 8.98 (s, 1H), 8.12 (d,1H, J=3.5 Hz), 7.58 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=2.3 Hz), 7.12 (dd,2H, J=2.3 and 8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 6.45 (d, 1H, J=8.8 Hz),4.91 (d, 1H, J=5.3 Hz), 4.65 (t, 1H, J=5.8 Hz), 3.92-3.89 (m, 1H),3.79-3.74 (m, 2H), 3.44 (t, 2H, J=5.3 Hz); LCMS: ret. time: 12.79 min.;purity: 89%; MS (m/e): 387 (MH⁺). 7.3.401 R935175:N2-[4-(2,3-Dihydroxypropoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isoproxyphenyl)-4-pyrimidineamine and4-(2,3-dihydroxypropoxy)aniline were reacted to produceN2-[4-(2,3-dihydroxypropoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine:¹H NMR (DMSO-d₆): δ9.12 (s, 1H), 8.91 (s, 1H), 7.97 (d, 1H, J=3.5 Hz),7.58 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz),6.76 (d, 2H, J=8.8 Hz); 4.89 (d, 1H, J=4.7 Hz), 4.63 (t, 1H, J=5.2 Hz),4.56 (septet, 1H, J=5.8 Hz), 3.90-3.89 (m, 1H), 3.76-3.73 (m, 2H), 3.41(t, 2H, J=5.3 Hz), 1.25 (d, 6H, J=5.8 Hz); LCMS: ret. time: 17.48 min.;purity: 98%; MS (m/e): 429 (MH⁺). 7.3.402 R935169:N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to produceN4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ7.87 (d, 1H, J=3.5 Hz), 7.56 (d, 2H, J=8.8 Hz), 7.35(d, 2H, J=8.8 Hz), 7.25-7.23 (m, 1H), 7.08 (t, 1H, J=8.2 Hz), 6.91 (d,1H, J=2.3 Hz), 6.83 (d, 1H, J=7.6 Hz), 6.50 (dd, 1H, J=1.7 and 8.2 Hz),4.13 (qt, 2H, J=7.0 Hz), 1.58 (s, 6H), 1.19 (t, 3H, J=7.0 Hz); LCMS:ret. time: 22.97 min.; purity: 98%; MS (m/e): 411 (MH⁺). 7.3.403R935164:5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[(N-methyl-2-methoxycarbonyl)pyrrol-4-yl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine,2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and andN-methyl-2-methoxycarbonyl-4-aminopyrrole hydrochloride with addeddiisopropylethylamine were reacted to produce the desired product5-fluoro-N4-(4-isopropoxyphenyl)-N2-[(N-methyl-2-carbomethoxy)pyrrol-4-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.87 (br s, 1H), 7.44 (d, 2H, J=8.8 Hz), 7.08 (br s,1H), 6.99-6.85 (m, 3H), 6.70 (d, 1H, J=2.3 Hz), 6.63 (d, 1H, J=1.7 Hz),4.52 (septet, 1H, J=5.8 Hz), 3.80 (s, 3H), 3.79 (s, 3H), 1.34 (d, 6H,J=5.8 Hz); LCMS: ret. time: 23.89 min.; purity: 99%; MS (m/e): 400(MH⁺). 7.3.404 R935165:5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[(N-methyl-2-carbomethoxy)pyrrole-4-yl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidineamineand 4-isopropoxyaniline were reacted to produce5-fluoro-N2-(4-isopropoxyphenyl)-N4-[(N-methyl-5-carbomethoxy)pyrrol-4-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.84 (d, 1H, J=2.3 Hz), 7.36 (d, 2H, J=8.8 Hz), 7.22(d, 1H, J=1.1 Hz), 6.87 (d, 2H, J=8.8 Hz), 6.84 (s, 1H), 6.77 (d, 1H,J=1.7 Hz), 6.61 (br s, 1H), 4.49 (septet, 1H, J=5.8 Hz), 3.82 (d, 3H),3.81 (s, 3H), 1.33 (d, 6H, J=5.8 Hz); LCMS: ret. time: 23.36 min.;purity: 96%; MS (m/e): 400 (MH⁺). 7.3.405 R935166:N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[(N-methyl-2-methoxycarbonyl)pyrrol-4-yl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-2-methoxycarbonylpyrrol-2-yl)-4-pyrimidineamineand 3,4-ethylenedioxyaniline were reacted to produce5-fluoro-N2-(3,4-ethylenedioxyphenyl)-N4-[(N-methyl-2-carbomethoxy)pyrrol-4-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.84 (d, 1H, J=3.5 Hz), 7.34 (s, 1H), 7.21 (s, 1H),6.82 (d, 2H, J=8.8 Hz), 6.76 (d, 2H, J=8.8 Hz), 6.58 (s, 1H), 4.27-4.18(m, 4H), 3.90 (s, 3H), 3.81 (s, 3H); LCMS: ret. time: 20.02 min.;purity: 93%; MS (m/e): 400 (MH⁺). 7.3.406 R935167:N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[4-[1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-4-pyrimidineamineand 4-isopropoxyaniline were reacted to produceN4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.29 (s, 1H), 8.95 (s, 1H), 8.02 (d, 1H, J=4.1 Hz),7.68 (d, 2H, J=8.8 Hz), 7.46 (d, 2H, J=8.8 Hz), 7.22 (d, 2H, J=8.8 Hz),6.75 (d, 2H, J=8.8 Hz), 4.48 (septet, 1H, J=5.8 Hz), 4.04 (qt, 2H, J=7.0Hz), 1.47 (s, 6H), 1.22 (d, 6H, J=5.8 Hz), 1.10 (t, 3H, J=7.0 Hz); LCMS:ret. time: 28.11 min.; purity: 99%; MS (m/e): 453 (MH⁺). 7.3.407R935159:5-Fluoro-N4-(4-isopropoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-hydroxyphenyl]-pyrimidine-2,4-diamine,2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and methl4-aminophenoxyacetate were reacted to produce5-fluoro-N4-(4-isopropoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.88 (d, 1H, J=3.5 Hz), 7.46 (d, 2H, J=8.8Hz), 7.42 (d,2H, J=8.8 Hz), 6.88 (d, 2H, J=9.3 Hz), 6.85 (d, 2H, J=9.3 Hz), 6.78 (brs, 1H), 6.63 (br d, 1H, J=2.3 Hz), 4.61 (s, 2H), 4.53 (septet, 1H, J=6.4Hz), 3.81 (s, 3H), 1.35 (d, 6H, J=6.4 Hz); LCMS: ret. time: 23.19 min.;purity: 97%; MS (m/e): 427 (MH⁺). 7.3.408 R935157:N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-hydroxyphenyl]-pyrimidine-2,4-diamine,2-chloro-N4-[4-[1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-4-pyrimidineaminewas reacted with 4-(methoxycarbonylmethyleneoxy)aniline to produceN4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.92 (s, 1H), 7.55 (d, 2H, J=8.7 Hz), 7.43 (d, 2H,J=9.3 Hz), 7.33 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=9.3 Hz), 6.79 (s, 1H),6.73 (d, 1H, J=2.3 Hz), 4.62 (s, 2H), 4.13 (qt, 2H, J=7.0 Hz), 3.81 (s,3H), 1.59 (s, 6H), 1.20 (t, 3H, 7.0 Hz); LCMS: ret. time: 25.20 min.;purity: 97%; MS (m/e): 483 (MH⁺). 7.3.409 R935152:N2-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN2-[4-(1-ethoxycarbonyl-1-methyl)ethyl)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and4-[1-ethoxycarbonyl-1-methyl)ethyl]aniline were reacted to giveN2-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.89 (d, 1H, J=2.9 Hz), 7.24-7.10 (m, 5H), 6.93 (d, 1H,J=7.6 Hz), 6.68 (d, 2H, J=8.2 Hz), 4.08 (qt, 2H, J=7.0 Hz), 1.52 (s,3H), 1.49 (s, 3H), 1.16 (t, 3H, J=7.0 Hz); LCMS: ret. time: 22.15 min.;purity: 96%; MS (m/e): 411 (MH⁺). 7.3.410N2-(3-tert-Butylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940257) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-tert-buthylaniline gaveN2-(3-tert-butylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.82 min.; purity: 100%; MS (m/e): 353 (MH⁺); ¹H NMR(CDCl₃): δ7.96 (1H, d, J=3 Hz), 7.61 (1H, ddd, J=7.5, 2.2 and 0.9 Hz),7.49 (1H, t, J=2.5 Hz), 7.27 (1H, m), 7.18 (1H, t, J=8.1 Hz), 7.99 (1H,m), 6.94 (1H, s), 6.91 (1H, dd, J=7.5 and 2.5 Hz), 6.80 (1H, d, J=7.5Hz), 6.72 (2H, m), 6.58 (1H, ddd, J=7.5, 2.5 and 0.9 Hz), 6.52 (1H, ddd,J=7.5, 2.5 and 0.9 Hz), 1.28 (9H, s). 7.3.411N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineandN4-(3-chloro-4-hydroxy-5-methylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940258) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-4-pyrimidineaminewith ethyl 3-aminophenoxyacetate gave a mixture ofN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineandN4-(3-chloro-4-hydroxy-5-methylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.34 min. (CO₂Me); purity: 17%; MS (m/e): 432 (M⁺);LCMS: ret. time: 21.83 min; purity 78%; MS (m/e): 446 (M⁺). 7.3.412N2-(3-tert-Butylphenyl)-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940260) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3,4-dimethoxyphenyl)-4-pyrimidineamine with ethyl3-tert-buthylaniline gaveN2-(3-tert-butylphenyl)-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 24.87 min.; purity: 99%; MS (m/e): 397 (MH⁺); ¹H NMR(CDCl₃): δ7.92 (1H, d, J=3.4 Hz), 7.50 (1H, d, J=8 Hz), 7.28 (1H, t,J=2.3 Hz), 7.21 (1H, d, J=8 Hz), 718 (1H, m), 7.08-7.01 (2H, m), 6.99(1H, s), 6.84 (2H, d, J=9.2 Hz), 6.65 (1H, s), 3.89 (3H, s), 3.72 (3H,s), 1.26 (9H, s). 7.3.413N2-[2-(N-Benzylpiperazino)ethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940261) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 4-(N-benzylpiperazino)ethylamine gaveN2-[2-(N-benzylpiperazino)ethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 17.15 min.; purity: 90 %; MS (m/e): 422 (M⁺), 423(MH⁺); ¹H NMR(CDCl₃): δ8.42 (1H, s), 7.82 (1H, d, J=3.9 Hz), 7.32-7.08(6H, m), 6.73 (1H, s), 6.61 (1H, dd, J=8.1 and 2.1 Hz), 6.51 (1H, d,J=7.5 Hz), 5.18 (1H, s), 3.59 (2H, m), 3.02 (2H, m), 2.71-2.41 (3H, m),2.10-1.16 (5H, m). 7.3.414N2-[2-(N-Benzylpiperazino)ethyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940262) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3,4-dimethoxyphenyl)-4-pyrimidineamine with4-(N-benzylpiperazino)ethylamine gaveN2-[2-(N-benzylpiperazino)ethyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 17.48 min.; purity: 99 %; MS (m/e): 466 (M⁺), 467(MH⁺); ¹H NMR (CDCl₃): δ7.82 (1H, d, J=3.9 Hz), 7.44 (1H, s), 7.33-7.10(6H, m), 7.04 (1H, dd, J=8.9 and 2.5 Hz), 6.84 (1H, d, J=8.9 Hz), 6.58(1H, s), 5.40 (1H, s), 3.91 (3H, s), 3.87 (3H, s), 3.41 (2H, m), 2.87(2H, m), 2.51 (3H, m), 1.80 (2H, m), 1.60 (4H, m), 1.30 (1H, m). 7.3.415N2-[4-(N-Benzylpiperidino)]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940263) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(3,4-dimethoxyphenyl)-4-pyrimidineamine withN-benzyl-4-aminopiperidine gaveN2-[4-(N-benzylpiperidino)]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.52 min.; purity: 99 %; MS (m/e): 438 (MH⁺); ¹HNMR(CDCl₃): δ7.81 (1H, d, 3.3 Hz), 7.35-7.18 (5H, m), 7.10 (1H, dd,J=8.7 and 2.6 Hz), 6.84 (1H, d, J=8.7 Hz), 6.56 (1H, s), 4.73 (1H, d,J=6.9 Hz), 3.89 (6H, s), 3.75 (1H, m), 3.51 (2H, m), 2.81 (2H, m), 2.15(2H, m), 2.00 (2H, m), 1.66-1.44 (4H, m). 7.3.416N2-[4-(N-Benzylpiperidino)]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940264) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith N-benzyl-4-aminopiperidine gaveN2-[4-(N-benzylpiperidino)]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 14.00 min.; purity: 96 %; MS (m/e): 394 (M⁺), 395(MH⁺); ¹H NMR(CDCl₃): δ7.81 (1H, d, J=3.6 Hz), 7.40-7.28 (5H, m),7.21-7.14 (2H, m), 6.69 (1H, m), 6.62 (1H, m), 6.59 (1H, m), 5.20 (1H,s), 3.65 (2H, s), 3.50 (1H, s), 3.03 (1H, m), 2.83 (1H, m), 2.13 (1H,m), 1.95-1.70 (1H, m), 1.58 (4H, m). 7.3.417N4-(3-tert-Butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940270) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine with ethyl3-aminophenoxyacetate gaveN4-(3-tert-butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 27.30 min.; purity: 98 %; MS (m/e): 439 (MH⁺); ¹H NMR(DMSO-d₆): δ9.50 (1H, s), 9.33 (1H, s), 8.11 (1H, dd, J=4.2 and 1.8 Hz),7.81 (1H, d, J=7.2 Hz), 7.49 (1H, t, 2.4 Hz), 7.30-7.28 (3H, m),7.14-7.03 (2H, m), 6.46 (1H, d, J=7.8 Hz), 4.57 (2H, s), 4.13 (2H, q,J=7.2 Hz), 1.23 (9H, s), 1.18 (3H, t, J=7.2 Hz). 7.3.418N4-(3-tert-Butylphenyl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R940271) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine with3-chloro-4-hydroxy-5-methylaniline gaveN4-(3-tert-butylphenyl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 25.46 min.; purity: 100 %; MS (m/e): 400 (M⁺); ¹H NMR(DMSO-d₆): δ9.63 (1H, s), 9.30 (1H, s), 8.82 (1H, s), 8.20 (1H, d, J=3.9Hz), 7.92 (1H, d, J=8,8 Hz), 7.58 (2H, m), 7.40-7.20 (3H, m) 2.22 (3H,s), 1.35 (9H, s). 7.3.419N2-(3-tert-Butylcarbonylaminophenyl)-N4-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940275) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-butylcarbonylaminoaniline gaveN2-(3-tert-butylcarbonylaminophenyl)-N4-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.19 min.; purity: 91 %; MS (m/e): 396 (MH⁺); 1H NMR(DMSO-d₆): δ9.42 (1H, s), 9.28 (1H, s), 9.21 (1H, s), 9.18 (1H, s), 8.17(1H, d, J=3.9 Hz), 7.90 (1H, s), 7.55 (1H, dt, J=6.9 and 2.1 Hz), 7.51(1H, dd, J=7.8 and 1.5 Hz), 7.26-7.13 (4H, m), 6.57 (1H, dd, J=7.5 and1.5 Hz), 1.30 (9H, s). 7.3.420N4-(3,3-Dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940294 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-4-pyrimidineamineand 2-methoxycarbonyl-5-aminobenzofuran were reacted to give N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 21.34 min.; purity: 97 %; MS (m/e): 434 (M⁺); 1H NMR(DMSO-d₆): δ9.90 (1H, s), 9.61 (1H, s), 8.4-8.12 (4H, m), 7.35-7.67 (4H,m), 5.50 (2H, s), 3.98 (3H, s). 7.3.421N2-[3-Ethoxycarbonylmethyleneoxyphenyl]-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-2,4-pyrimidinediamineR940285 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-4-pyrimidineamineand ethyl 3-aminophenoxyacetate were reacted to giveN2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.55 min.; purity: 76 %; MS (m/e): 438 (M⁺), 440(MH⁺); 1H NMR (DMSO-d₆): δ9.70 (1H, s), 9.30 (1H, s), 8.23-8.06 (1H, m),8.05 (1H, s), 7.63 (1H, d, J=8.1 Hz), 7.30 (1H, s), 7.22 (1H, m), 7.08(1H, t, J=8.1 Hz), 6.43 (1H, d, J=8.1 Hz), 5.37 (1H, s), 5.37 (2H, s),4.60 (2H, s), 4.13 (2H, q, J=7.2 Hz), 1.18 (3H, t, J=7.2 Hz). 7.3.422N2-(3,5-Dimethoxyphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926804) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3,5-dimethoxyaniline gaveN2-(3,5-dimethoxyphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 24.12 min.; purity: 86%; MS (m/e): 443 (MH⁺). 7.3.423N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-trifluoromethylphenyl)]-2,4-pyrimidinediamine(R926805) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-trifluoromethylaniline gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-trifluoromethylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 25.88 min.; purity: 89%; MS (m/e): 407 (MH⁺). 7.3.424N2-(2-Ethoxycarbonylindol-7-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine(R926808) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with2-ethoxycarbonyl-7-aminoindole gaveN2-(2-ethoxycarbonylindol-7-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine.LCMS: ret. time: 24.11 min.; purity: 88%, MS (m/e): 450 (MH⁺). 7.3.425N4-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926809) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN-4-[4-(4,5-dichloro-1H-imidazol-1-yl)phenyl]-2-chloro-5-fluoro-4-pyrimidineaminewith ethyl-3-aminophenoxyacetate gaveN4-[4-(4,5-dichloro-1H-imidazol-1-ylphenyl)]-5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 25.22 min, purity: 77%; MS (m/e): 519 (MH⁺). 7.3.426N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926813) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-(1,3-oxazol-5-yl)aniline gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 20.25 min.; purity: 81%, MS (m/e): 406 (MH⁺). 7.3.427N2-(2-Ethoxycarbonylindol-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyridinediamine(R926814) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 2-ethoxycarbonyl-7-aminoindol gaveN2-(2-ethoxycarbonylindol-7-yl)-5-fluoroN4-(3-hydroxyphenyl)-2,4-pyridinediamine. LCMS: ret. time: 25.94 min.;purity: 91%. 7.3.428N2-(3-Aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950207)N4-(3,4-Ethylenedioxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine (50 mg,0.18 mmol) was dissolved in dry MeOH (1 ml), to it was added3-aminoaniline (163 mg, 1.2 mmol) and the mixture was refluxed for 4days (70° C. oil-bath temperature). The mixture was cooled to 22° C.,concentrated to dryness under reduced pressure and subjected to columnchromatography on silica gel (CHCl₃-Acetone, 9:1) to giveN2-(3-aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.66 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=2.1 Hz), 7.09(t, 1H, J=2.1 Hz), 6.80-6.90, (m, 1H), 6.69 (d, 1H, J=8.1 Hz), 6.57 (m,1H), 6.20 (m, 1H), 6.60 (m, 1H), 4.10 (m, 4H); LCMS purity: 90.7%; MS(m/e): 354.13 (M⁺, 100). 7.3.429N4-(3,4-Ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine(R950186) In like manner to the preparation ofN2-(3-aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine and3-ethoxycarbonylmethyleneaminophenylaniline were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 23.29 min.; purity: 95.7%; MS (m/e): 440.41 (MH⁺).7.3.430N4-(3,5-Dichloro-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950185) In like manner to the preparation ofN2-(3-aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,5-dichlorophenyl-4-hydroxy)-5-fluoro-4-pyrimidineamineand ethyl 3-aminophenoxyacetate were reacted to prepareN4-(3,5-dichloro-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.51 min.; purity: 96.1%; MS (m/e): 466.88 (MH⁺).7.3.431N4-(3-Aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-2,4-pyrimidinediamine(R950162) A mixture ofN4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine (10 mg, 0.06mmol) and 2-methoxycarbonyl-5-aminobenzofuran (36 mg, 0.18 mmol) in dryMeOH (0.5 ml) was refluxed for 2 days (100° C. oil-bath temperature).The mixture was cooled to 22° C., concentrated to dryness under reducedpressure and subjected to column chromatography on silica gel(CHCl₃:Acetone, 9:1) to giveN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.24 (s, 1H), 7.96 (dd, 1H, J=1.7, 3.5 Hz), 7.46-7.59(m, 3H), 6.93-6.99 (m, 2H), 6.84 (d, 1H, J=8.2 Hz), 6.35 (m, 1H), 3.84(s, 3H); LCMS purity: 97.8%; MS (ES) m/e 394.02 (M⁺, 70). 7.3.432N4-(3-Aminophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950163) In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine and3-hydroxyaniline were reacted to prepareN4-(3-aminophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ7.94 (d, 1H, J=4.1 Hz), 7.20 (m, 2H), 6.89-7.00 (m,4H), 6.30 (m, 2H); LCMS: ret. time: 11.92 min.; purity: 95.0%; MS (m/e):312.09 (MH⁺). 7.3.433N4-(3-Aminophenyl)-5-fluoro-N2-(3-isopropoxyphenyl)-2,4-pyrimidinediamine(R950164) In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine and3-isopropoxyaniline were reacted to prepareN4-(3-aminophenyl)-5-fluoro-N2-(3-isopropoxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 17.52 min.; purity: 98.9%; MS (m/e): 354.13 (MH⁺).7.3.434N4-(3-Aminophenyl)-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R950165) In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine and4-isopropoxyaniline were reacted to prepareN4-(3-aminophenyl)-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-D6-MeOD, 300 MHz): δ7.90 (d, 1H, J=4.1 Hz), 7.47 (m, 2H),7.03 (t, 1H, J=1.7 Hz), 6.60-6.95 (m, 5H), 6.29 (m, 1H), 4.43 (septett,1H, J=6.0 Hz), 1.18 (d, 6H, J=6.0 Hz); LCMS: ret. time: 17.11 min.;purity: 88.4%; MS (m/e): 354.09 (MH⁺). 7.3.435N2-(3-Furylmethylene)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950210) In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-furylmathylamine were reacted to prepareN2-(3-furylmethylene)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 16.03 min.; purity: 93.5%; MS (m/e): 301.10 (MH⁺).7.3.4365-Fluoro-N4-(3-hydroxyphenyl)-N2-(4-methoxyphenyloxyethyleneamino)-2,4-pyrimidinediamine(R950211) In like manner to the preparation ofN4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and2-(4-methoxyphenyl)ethylamine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-(4-methoxyphenyloxyethyleneamino)-2,4-pyrimidinediamine.LCMS: ret. time: 18.88 min.; purity: 97.6%; MS (m/e): 371.09 (MH⁺).7.3.437N4-(3-Aminophenyl)-N2-[[N3-[N4-(3-aminophenyl)]-5-fluoro-2,4-pyrimidinediamine]aminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950137) 2,4-Dichloro-5-fluoropyrimidine and 3-aminoaniline werereacted to prepareN4-(3-aminophenyl)-N2-[[N3-[N4-(3-aminophenyl)]-5-fluoro-2,4-pyrimidinediamine]aminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.10 min.; purity: 96.4%; MS (m/e): 513.01 (MH⁺).7.3.438N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(hydroxyethyleneamino)phenyl]-2,4-pyrimidinediamine(R950208)N2-(3-Aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand 2-bromoethanol were reacted together to giveN4-(3,4-ethylenedioxyphenyl)-N2-[3-(hydroxyethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.44 min.; purity: 98.6%; MS (m/e): 398.05 (MH⁺).7.3.439N2-[3-Bis(hydroxyethyl)aminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950209)N2-(3-Aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand 2-bromoethanol were reacted together to giveN2-[3-bis(hydroxyethyl)aminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.64 min.; purity: 97.8%; MS (m/e): 442.06 (MH⁺).7.3.4406-Ethoxycarbonyl-N4-(ethoxycarbonylmethyl)-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-5-nitro-2,4-pyrimidinediamine(R925858) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-hydroxyphenyl)-2,4-pyrimidinediamine,N-(2-chloro-6-ethoxycarbonyl-5-nitro-4-pyrimidinyl)glycine ethyl esterand ethyl 4-aminophenoxyacetate were reacted to yield6-ethoxycarbonyl-N4-(ethoxycarbonylmethyl)-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-5-nitro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ9.00 (bs, 1H), 7.49 (bs, 1H), 7.41 (d, 2H, J=9.0 Hz),6.89 (d, 2H, J=9.0 Hz), 4.62 (s, 2H), 4.46 (q, 2H, J=7.2 Hz), 4.31-4.19(m, 6H), 1.40 (t, 3H, J=7.2 Hz), 1.33-1.25 (m, 6H); LCMS: ret. time:30.00 min.; purity: 98 %; MS (m/e): 492 (MH⁺). 7.3.441N4-Benzyloxy-5-ethoxycarbonyl-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine(R925837) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-benzyloxy-2-chloro-5-ethoxycarbonyl-4-pyrimidineamine and1,4-benzodioxan-6-amine were reacted to yieldN4-benzyloxy-5-ethoxycarbonyl-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.55 (s, 1H), 7.49-7.44 (m, 3H), 7.39-7.34 (m, 4H),7.30-7.22 (m, 1H), 6.67 (d, 1H, J=8.4 Hz), 4.98 (s, 2H), 4.23-4.17 (m,6H), 1.26 (t, 3H, J=7.2 Hz); LCMS: ret. time: 26.14 min.; purity: 95%;MS (m/e): 423 (MH⁺). 7.3.442N4-Benzyloxy-5-ethoxycarbonyl-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925824) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-benzyloxy-2-chloro-5-ethoxycarbonyl-4-pyrimidineamine and3-hydroxyaniline were reacted to yieldN4-benzyloxy-5-ethoxycarbonyl-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 24.28 min.; purity: 88 %; MS (m/e): 381 (MH⁺). 7.3.443N2,N4-Bis[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945025) A mixture of 4-nitrophenol (7.65 g, 55 mmol), 2-bromoacetamide(6.90 g, 50 mmol) and K₂CO₃ (13.8 g, 0.1 mol) in acetone (50 mL) wasstirred at room temperature for 24 h. The reaction mixture was dilutedwith water, and acetone was removed under reduced pressure. The formedlight-yellow precipitate was collected by filtration, washed with waterand dried to give 1-aminocarbonylmethyleneoxy-4-nitrobenzene (8.28 g,84%). Hydrogenation of 1-aminocarbonylmethyleneoxy-4-nitrobenzene (3 g,15 mmol) in methanol (50 mL) catalyzed by 10% Pd-C (500 mg) and Na₂SO₄(500 mg) at 50 psi for 2 h gave 4-(aminocarbonylmethyleneoxy)aniline(2.59 g, quant.). 4-(Aminocarbonylmethyleneoxy)aniline (500 mg, 3 mmol)and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) were dissolved inmethanol (10 mL) and water (1 mL) and was stirred at 70° C. for 24 h.Then methanol was removed under reduced pressure. The remaining aqueoussolution was acidified with 1 N HCl (80 mL). The formed whiteprecipitate was collected by filtration to giveN2,N4-bis[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(370 mg, 72%). ¹H NMR (acetone-d ₆): δ4.46 (s, 2H), 4.50 (s, 2H), 6.81(br, NH, 2H), 6.91 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 7.20 (br,2H, NH), 7.63 (d, J=9.3 Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 7.93 (d, J=3.6Hz, 1H), 8.27 (br, 1H, NH), 8.44 (br, 1H, NH); LCMS: ret. time: 13.91min.; purity: 100%; MS (m/e): 427.02 (MH⁺). 7.3.444N2,N4-Bis[4-(cyanomethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945032) To a solution ofN2,N4-bis[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(200 mg, 0.47 mmol) in THF (10 mL) was added trifluoroacetic anhydride(0.33 mL, 2.35 mmol) and pyridine (0.38 mL, 4.7 mmol) at roomtemperature and was stirred at room temperature overnight. The mixturewas diluted with ethyl acetate (80 mL) and 1 N HCl (80 mL). The organiclayer was washed with 1 N HCl (2 × 60 mL), water (2 × 60 mL) and brine(60 mL). The ethyl acetate layer was dried and evaporated. The residuewas recrystallized from ethyl acetate and hexanes to giveN2,N4-bis[4-(cyanomethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(159 mg, 87%) as a white solid. ¹H NMR (acetone-d ₆): δ5.09 (s, 2H),5.16 (s, 2H), 7.08 (d, J=9.3 Hz, 2H), 7.17 (d, J=9.0 Hz, 2H), 7.63 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.3 Hz, 2H), 8.17 (d, J=4.8 Hz, 1H), 9.55 (br,1H, NH), 11.00 (br, 1H, NH); LCMS: 21.47 min.; 96.11%; MS (m/e): 391.20(MH⁺). 7.3.4456N2,N4-Bis[4-(1H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R945033) To a solution ofN2,N4-bis[4-(cyanomethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(100 mg, 0.26 mmol) in DMF (10 mL) was added NH₄Cl (136 mg, 2.54 mmol),sodium azide (100 mg, 1.54 mmol), and one drop of acetic acid and wasstirred at 70° C. overnight. Then it was titrated with ethyl acetate (80mL) to give precipitation. The precipitate was collected by filtration,washed with 1 N HCl and water to giveN2,N4-bis[4-(1H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(66 mg, 54%) as a white solid. ¹H NMR (CD₃OD): δ5.31 (s, 2H), 5.34 (s,2H), 6.93 (d, J=9.0 Hz, 2H), 7.00 (d, J=9.3 Hz, 2H), 7.04 (d, J=9.0 Hz,2H), 7.57 (d, J=9.0 Hz, 2H), 7.81 (d, J=4.2 Hz, 1H); LCMS: 16.54 min.;purity: 88.34%; MS (m/e): 477.02 (MH⁺). 7.3.446N2,N4-Bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945034) A mixture of 4-Aminobenzoic acid (410 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) in methanol (10 mL)and water (1 mL) was stirred at 100° C. for 24 h to yieldN2,N4-bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine after methanolwas removal. This residue was redissolved in DMF (10 mL) and to it wasadded potassium carbonate (1.65 g, 12 mmol) and iodomethane (0.37 mL, 6mmol), stirred at room temperature overnight, and then diluted with 1 NHCl (80 mL) and ethyl acetate (80 mL). The ethyl acetate layer waswashed with 1N HCl (60 mL) and water (60 mL). The organic layer wasseparated, dried, evaporated and the resulting residue wasrecrystallized from ethyl acetate/hexanes to giveN2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (150mg, 63%). ¹H NMR (acetone-d ₆): δ3.85 (s, 3H), 3.88 (s, 3H), 7.88-7.97(m, 4H), 7.98-8.05 (m, 4H), 8.18 (d, J=3.0 Hz, 1H), 9.00 (br, 1H, NH),9.04 (br, 1H, NH); LCMS: ret. time: 27.07 min.; purity: 95.54%; MS(m/e): 397.04 (MH⁺). 7.3.447N2,N4-Bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945035) In a manner analogous to the preparation ofN2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine, thereaction of 3-aminobenzoic acid (410 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (180mg, 76%) as a white solid. ¹H NMR (acetone-d ₆): δ3.81 (s, 3H), 3.83 (s,3H), 7.37 (t, J=8.1 Hz, 1H), 7.47 (t, J=8.1 Hz, 1H), 7.60 (d, J=7.8 Hz,1H), 7.75 (d, J=7.5 Hz, 1H), 8.02 (d, J=6.3 Hz, 1H), 8.10 (d, J=3.6 Hz,1H), 8.24 (d, J=8.4 Hz, 1H), 8.36 (d, J=11.4 Hz, 2H), 8.74 (br, 1H, NH),8.82 (br, 1H, NH); LCMS: ret. time: 22.77 min.; purity: 91.04%; MS(m/e): 397.00 (MH⁺). 7.3.448N2,N4-Bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R945036) Asolution ofN2,N4-bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (100mg, 0.25 mmol) and NaOH (140 mg, 3.5 mmol) in THF:H₂O (5 mL, each) wasstirred at room temperature overnight. The reaction mixture was dilutedwith water (60 mL) and ethyl acetate (60 mL). The aqueous layer wasseparated, acidified with 1N HCl solution to pH 3. The formedprecipitate was collected by filtration and recrystallized from methanolto give N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (54mg, 58%) as a white solid. ¹H NMR (CD₃OD): δ7.31 (t, J=8.1 Hz, 1H), 7.42(t, J=8.1 Hz, 1H), 7.61 (dm, J=7.8 Hz, 1H), 7.76 (dm, J=8.4 Hz, 1H),7.89 (dm, J=7.2 Hz, 1H), 7.98 (d, J=3.6 Hz, 1H), 8.01 (m, 1H), 8.20 (m,1H), 8.37 (m, 1H); LCMS: ret. time: 15.77 min.; purity: 98.84%; MS(m/e): 369.03 (MH⁺). 7.3.449N2,N4-Bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R945037) In amanner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (100mg, 0.25 mmol) and NaOH (200 mg, 5 mmol) gaveN2,N4-bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (55 mg, 59%)as a white solid. ¹H NMR (CD₃OD): δ7.77 (d, J=8.7 Hz, 2H), 7.92 (d,J=8.7 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.7 Hz, 2H), 8.07 (d,J=3.6 Hz, 1H); LCMS: ret. time: 16.34 min.; purity: 100%; MS (m/e):368.87 (MH⁺). 7.3.450N2,N4-Bis(3-isopropylaminocarbonyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926412) The reaction of 1 equivalent ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine with 3equivalents of isopropyl isocyanate in the presence of pyridine inCH₂Cl₂ at room temperature for 24 h followed by extractive work up usingCH₂Cl₂ gave the desiredN2,N4-bis(3-isopropylaminocarbonyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃ + CD₃OD): δ7.82 (d, 1H, J=3.6 Hz), 7.66 (bd, 1H), 7.48(bd, 1H). 7.15-7.02 (m, 2H), 6.76-6.76 (m, 2H), 6.56 (bd, 1H, J=8.1 Hz),6.45 (dd, 1H, J=1.8 and 8.4 Hz), 4.70 (m, 2H), 1.05 (d, 12H, J=6.3 Hz);¹⁹F NMR (CDCl₃ + CD₃OD): - 47206; LCMS: ret. time: 15.40 min.; purity:90%. 7.3.451N2,N4-Bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945040) A mixture of 1,4-diaminobenzene (4 g, 37 mmol), ethylisocyanate (1 mL, 12.6 mmol) and potassium carbonate (8.72 g, 63 mmol)in THF (20 mL) was stirred at room temperature overnight. The reactionmixture was partitioned in 1N HCl solution (80 mL) and ethyl acetate (80mL). The aqueous layer was extracted with ethyl acetate (4 × 80 mL). Thecombined organic layers was dried, evaporated, recrystallized fromMeOH/CH₂Cl₂/hexanes to give 4-(ethylaminocarbonylamino)aniline (1.4 g,62%) as a beige solid. In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,4-(ethylaminocarbonylamino)aniline (537 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(180 mg, 66%) as a white solid. ¹H NMR (CD₃OD): δ1.16 (t, J=7.2 Hz, 6H),3.24 (q, J=7.2 Hz, 4H), 7.29 (d, J=9.0 Hz, 2H), 7.40 (t, J=9.0 Hz, 4H),7.55 (d, J=9.0 Hz, 2H), 7.87 (s, 1H, NH), 7.89 (s, 1H, NH); LCMS: ret.time: 16.93 min.; purity: 93.43%; MS (m/e): 453.03 (MH⁺). 7.3.452N2,N4-Bis[3-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945045) In a manner analogous to the preparation ofN2,N4-bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine,the reaction of 1,3-diaminobenzene (2 g, 18.5 mmol), ethyl isocyanate(0.5 mL, 6.3 mmol) and potassium carbonate (4.36 g, 31.5 mmol) gave3-(ethylaminocarbonylamino)aniline (940 mg, 83%). The reaction of3-(ethylaminocarbonylamino)aniline (537 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis[3-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine(180 mg, 66%) as a white solid. ¹H NMR (CD₃OD): δ1.14 (t, J=6.9 Hz, 3H),1.15 (t, J=7.5 Hz, 3H), 3.21 (q, J=7.2 Hz, 2H), 3.22 (q, J=7.5 Hz, 2H),7.06 (ddd, J=0.9, 2.1, 7.8 Hz, 1H), 7.10-7.28 (m, 5H), 7.53 (t, J=2.1Hz, 1H), 7.80 (m, 1H), 7.92 (d, J=5.7 Hz, 1H); LCMS: ret. time: 17.17min.; purity: 89.63%; MS (m/e): 453.38 (MH⁺). 7.3.453N2,N4-Bis(4-hydroxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945043) A solution ofN2,N4-bis(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (70mg, 0.17 mmol) and thionyl chloride (0.04 mL, 0.55 mmol) in MeOH (10 mL)was refluxed overnight. Methanol was removed in vacuo. The residue wasdiluted with EtOAc (60 mL) and sodium hydrogen carbonate solution (60mL). The EtOAc layer was washed with NaHCO₃ aqueous solution (60 mL) andwater (60 mL). The organic layer was dried, evaporated and crystallizedfrom MeOH/Et₂O to giveN2,N4-bis(4-hydroxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(58 mg, 77%). ¹H NMR (DMSO-d₆): δ3.69 (s, 3H), 3.71 (s, 3H), 6.81 (d,J=9.3 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H), 7.64 (dd, J=2.7, 9.0 Hz, 1H),7.84 (dd, J=2.1 and 8.4 Hz, 1 H), 8.03-8.07 (m, 3 H), 9.14 (s, 1 H, NH),9.34 (s, 1 H, NH), 10.16 (s, 1 H, OH), 10.29 (s, 1H, OH); ¹⁹F NMR (282MHz, DMSO-d₆): δ- 165.60; LCMS: ret. time: 22.24 min.; purity: 100%; MS(m/e): 428.98 (MH⁺). 7.3.454N2,N4-Bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R945046)5-Fluoro-N2,N4-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl],[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945047)N2,N4-Bis[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R945048) CompoundN2,N4-bis[4-(1H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(30 mg, 0.063 mmol), iodomethane (0.024 mL, 0.38 mmol) and K₂CO₃ (88 mg,0.64 mmol) in DMF (5 mL) was stirred at room temperature overnight. Thenit was diluted with ethyl acetate (50 mL) and water (50 mL). The organiclayer was washed with water (50 mL) and brine (50 mL). After separation,the ethyl acetate layer was dried, evaporated and purified by flashcolumn chromatography (EtOAc/hexanes =2/1, 1/1, EtOAc) to give a mixtureof following compounds:N2,N4-bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineR945046 (6 mg, 19%), ¹H NMR (CDCl₃): δ4.37 (s, 3H), 4.38 (s, 3H), 5.33(s, 2H), 5.36 (s, 2H), 6.65 (d, J=3.0 Hz, 1H), 6.76 (s, 1H), 6.98 (d,J=9.0 Hz, 2H), 7.04 (d, J=9.3 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H), 7.51 (d,J=9.0 Hz, 2H), 7.90 (br, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 168.52; LCMS:ret. time: 20.44 min.; purity: 94.92%; MS (m/e): 505.02 (MH⁺);5-fluoro-N2,N4-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl],[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineR945047 (8 mg, 25%), ¹H NMR (CDCl₃): δ4.18 (s, 3H), 4.20 (s, 3H), 4.36(s, 3H), 4.37 (s, 3H), 5.34 (s, 2H), 5.37 (s, 2H), 5.42 (s, 2H), 5.46(s, 2H), 6.69 (br, 2H), 6.80 (s, 1H), 6.83 (s, 1H), 6.91 (d, J=9.3 Hz,2H), 6.98 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.3 Hz, 2H), 7.04 (d, J=9.0 Hz,2H), 7.41 (d, J=9.9 Hz, 2H), 7.44 (d, J=9.3 Hz, 2H), 7.50 (d, J=9.0 Hz,2H), 7.54 (d, J=9.0 Hz, 2H), 7.91 (br, 2H); ¹⁹F NMR (282 MHz, CDCl₃): δ-168.39, - 168.16; LCMS: ret. time: 19.42 min.; purity: 91.18%; MS (m/e):504.99 (MH⁺), andN2,N4-bis[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineR945048 (6 mg, 19%), ¹H NMR (CD₃OD + CDCl₃): δ4.20 (s, 3H), 4.22 (s,3H), 5.50 (s, 2H), 5.55 (s, 2H), 6.95 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.3Hz, 2H), 7.52 (d, J=9.0 Hz, 2H), 7.66 (d, J=9.3 Hz, 2H), 7.84 (d, J=3.6Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD+CDCl₃): δ- 163.12; LCMS: ret. time:18.32 min.; purity: 83.41%; MS (m/e): 504.99 (MH⁺). 7.3.455N4-(4-Aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945052) In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,4-(aminocarbonylmethyleneoxy)aniline (398 mg, 2.4 mmol) and2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) gaveN4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(270 mg, 76%). In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof methyl 4-aminophenoxyacetate (183 mg, 1 mmol) andN4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine(100 mg, 0.34 mmol) gaveN4-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(120 mg, 80%). ¹H NMR (acetone-d ₆): δ3.25 (s, 3H), 3.98 (s, 2H), 4.33(s, 2H), 6.45 (d, J=8.7 Hz, 2H), 6.49 (d, J=9.3 Hz, 2H), 6.93 (d, J=8.7Hz, 2H), 7.13 (d, J=9.0 Hz, 2H), 7.71 (d, J=5.1 Hz, 1H), 9.46 (br, 1H,NH), 9.78 (br, 1H, NH); LCMS: ret. time: 16.65 min.; purity: 100%; MS(m/e): 442.01 (MH⁺). 7.3.456N4-(4-Cyanomethyleneoxyphenyl])5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945053) In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine, thereaction ofN4-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (80 mg, 0.18 mmol), trifluoroaceticanhydride (0.13 mL, 0.92 mmol) and pyridine (0.15 mL, 1.84 mmol) gaveN4-(4-cyanomethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(52 mg, 68%) as a white solid. ¹H NMR (DMSO-d₆): δ3.24 (s, 3H), 4.26 (s,2H), 4.71 (s, 2H), 6.36 (d, J=9.3 Hz, 2H), 6.59 (d, J=9.0 Hz, 2H), 7.06(d, J=9.0 Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 7.58 (d, J=3.6 Hz, 1H), 8.59(br, 1H, NH), 8.85 (br, 1H, NH); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 166.26;LCMS: ret. time: 21.37 min.; purity: 100%; MS (m/e): 424.01 (MH⁺).7.3.457N2,N4-Bis[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(R945056) A solution of 4-amino-2-hydroxybenzoic acid (1 g, 6.5 mmol) inMeOH (15 mL) and concentrated sulfonic acid (1 mL) was refluxedovernight. The reaction mixture was quenched with NaHCO₃ aqueoussolution (60 mL) and EtOAc (60 mL). The organic layer was separated,dried, evaporated to give 3-hydroxy-4-methoxycarbonylaniline. In amanner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,3-hydroxy-4-methoxycarbonylaniline (500 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis-[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(105 mg, 41%). ¹H NMR (DMSO-d₆): δ3.90 (s, 3H), 3.93 (s, 3H), 7.31 (dd,J=2.4, 9.0 Hz, 1H), 7.56 (dd, J=2.1, 8.7 Hz, 1H), 7.63 (d, J=2.1 Hz,1H), 7.67 (d, J=2.1 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.79 (d, J=9.0 Hz,1H), 8.28 (d, J=3.6 Hz, 1H), 9.72 (s, 1H, NH), 9.82 (s, 1H, NH), 10.77(s, 1H, OH), 10.80 (s, 1H, OH); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 161.74;LCMS: ret. time: 31.47 min.; purity: 96.03%; MS (m/e): 428.99 (MH⁺).7.3.458N2-(4-Aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945060) In a manner analogous to the preparation ofN4-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-4-pyrimidineamine(150 mg, 0.48 mmol) and 4-(aminocarbonylmethyleneoxy)aniline (240 mg,1.44 mmol) gaveN2-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (145 mg, 68%). ¹H NMR (DMSO-d₆): δ3.70(s, 3H), 4.40 (s, 2H), 4.81 (s, 2H), 6.91 (d, J=8.4 Hz, 2 H), 6.93 (d,J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.7 Hz, 2H), 8.21 (d,J=4.8 Hz, 1H), 10.13 (br, 1H, NH), 10.39 (br, 1H, NH); ¹⁹F NMR (282 MHz,DMSO-d₆): δ- 162.26; LCMS: ret. time: 15.37 min.; purity: 78.49%; MS(m/e): 442.07 (MH⁺). 7.3.459N2,N4-Bis(3-hydroxy-4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945061) In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionofN2,N4-bis[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(70 mg, 0.16 mmol) and NaOH (100 mg, 2.5 mmol) gaveN2,N4-bis(3-hydroxy-4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (50mg, 77%) as a white solid. ¹H NMR (DMSO-d₆): δ7.21 (dd, J=1.5 and 8.7Hz, 1H), 7.46-7.52 (m, 3H), 7.63 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz,1H), 8.28 (d, J=3.3 Hz, 1H), 9.71 (s, 1H, NH), 9.79 (s, 1H, NH), 11.34(br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 161.10; LCMS: ret. time: 20.76min.; purity: 84.65%; MS (m/e): 400.95 (MH⁺). 7.3.460N2-(4-Cyanomethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945062) In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(100 mg, 0.23 mmol), trifluoroacetic anhydride (0.16 mL, 1.13 mmol) andpyridine (0.18 mL, 2.21 mmol) gaveN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(66 mg, 69%) as a white solid. ¹H NMR (acetone-d ₆): δ3.75 (s, 3H), 4.67(s, 2H), 4.89 (s, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.3 Hz, 2H),7.48 (d, J=9.0 Hz, 2H), 7.54 (d, J=9.0 Hz, 2H), 7.84 (d, J=4.2 Hz, 1H),9.17 (br, 1H, NH), 10.59 (br, 1H, NH); ¹⁹F NMR (282 MHz, acetone-d ₆):δ- 164.65; LCMS: ret. time: 20.69 min.; purity: 94.35%; MS (m/e): 424.02(MH⁺). 7.3.461N2,N4-Bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945065) In a manner analogous to the preparation ofN2,N4-bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine,2-methoxy-4-nitrobenzoic acid (1 g, 5 mmol), potassium carbonate (1.4 g,10 mmol) and iodomethane (0.47 mL, 7.5 mmol) gave methyl2-methoxy-4-nitrobenzoate (820 mg, 77%) as a white solid. Thehydrogenation of methyl 2-methoxy-4-nitrobenzoate (700 mg, 3.3 mmol) inmethanol (10 mL) catalyzed by 5% Pd-C (100 mg) and Na₂SO₄ (100 mg) at 50psi for 1 h gave methyl 4-amino-2-methoxybenzoate (600 mg, quant.) as awhite solid. In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, methyl4-amino-2-methoxybenzoate (542 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(180 mg, 66%) as a white solid. ¹H NMR (acetone-d ₆): δ3.76 (s, 3H),3.77 (s, 3H), 3.81 (s, 6H), 7.36 (dd, J=1.8, 8.7Hz, 1H), 7.57 (s, 1H),7.58 (dd, J=2.1 and 7.2 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 8.17 (d, J=3.3 Hz, 1H), 8.89 (s, 2H,NH); ¹⁹F NMR (282 MHz, acetone-d ₆): δ- 165.18; LCMS: ret. time: 23.17min.; purity: 100%; MS (m/e): 456.96 (MH⁺). 7.3.462N2,N4-Bis(4-methoxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R945066) In a manner analogous to the preparation ofN2,N4-bis(3-methoxy-4-methoxycarbonyl)phenyl)-5-fluoro-2,4-pyrimidinediamine,2-hydroxy-5-nitrobenzoic acid (1 g, 5.5 mmol), potassium carbonate (3 g,22 mmol) and iodomethane (1 mL, 16 mmol) gave methyl2-hydroxy-5-nitrobenzoate (880 mg, 77%). The hydrogenation of methyl2-hydroxy-5-nitrobenzoate (700 mg, 3.3 mmol) using 10% Pd-C (100 mg) andNa₂SO₄ (100 mg) in MeOH at 50 psi gave methyl 5-amino-2-methoxybenzoate(600 mg). In a manner analogous to the preparation ofN2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, methyl5-amino-2-methoxybenzoate (542 mg, 3 mmol) and2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gaveN2,N4-bis(4-methoxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(170 mg, 62%) as a pink solid. ¹H NMR (acetone-d ₆): δ3.76 (s, 3H), 3.77(s, 3H), 3.88 (s, 3H), 3.93 (s, 3H), 7.08 (dd, J=0.8, 9.0 Hz, 1H), 7.18(d, J=9.0 Hz, 1H), 7.66 (dd, J=3.0 and 8.7 Hz, 1H), 7.78 (dd, J=1.5 and3.0 Hz, 1H), 7.86 (dt, J=2.7 and 9.0 Hz, 1H), 7.98 (t, J=2.7 Hz, 1H),8.32 (d, J=5.1 Hz, 1H); ¹⁹F NMR (282 MHz, acetone-d ₆): δ-163.88; LCMS:ret. time: 19.07 min.; purity: 98.17%; MS (m/e): 456.94 (MH⁺). 7.3.463N2,N4-Bis(3-carboxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945067) In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis[4-methoxy-3-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine(80 mg, 0.18 mmol) and NaOH (200 mg, 5 mmol) gaveN2,N4-bis(3-carboxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (80mg). ¹H NMR (DMSO-d₆): δ3.75 (s, 3H), 3.80 (s, 3H), 6.94 (d, J=9.6 Hz,1H), 7.05 (d, J=9.3 Hz, 1H), 7.78-7.80 (m, 3H), 7.94 (dd, J=9.3 Hz, 1H),8.04 (d, J=3.6 Hz, 1H), 9.10 (s, 1H, NH), 9.30 (s, 1H, NH); ¹⁹F NMR (282MHz, DMSO-d₆): δ- 165.56; LCMS: ret. time: 14.65 min.; purity: 100%; MS(m/e): 428.83 (MH⁺). 7.3.464N2,N4-Bis(4-carboxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945068) In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2,N4-bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(30 mg, 0.06 mmol) and NaOH (200 mg, 5 mmol) gaveN2,N4-bis(4-carboxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (18mg, 64%) as a white solid. ¹H NMR (DMSO-d₆): δ3.66 (s, 3H), 3.73 (s,3H), 7.37 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.49 (s, 1H), 7.61-7.71 (m,3H), 8.25 (d, J=3.6 Hz, 1H), 9.65 (s, 1H, NH), 9.70 (s, 1H, NH); ¹⁹F NMR(282 MHz, DMSO-d₆): δ- 162.11; LCMS: ret. time: 17.25 min.; purity:100%; MS (m/e): 429.04 (MH⁺). 7.3.465N2-(4-Cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945070) In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N2-(4-(aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(60 mg, 0.16 mmol), trifluoroacetic anhydride (0.11 mL, 0.8 mmol) andpyridine (0.13 mL, 1.6 mmol) gaveN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(30 mg, 53%). ¹H NMR (acetone-d ₆): δ5.04 (s, 2H), 6.60 (ddd, J=0.9, 2.4and 8.1 Hz, 1H), 7.02 (d, J=9.3 Hz, 2H), 7.15 (t, J=8.1 Hz, 1H), 7.31(ddd, J=1.2, 2.1 and 8.1 Hz, 1H), 7.38 (t, J=2.1 Hz, 1H), 7.78 (d, J=9.3Hz, 2H), 7.98 (d, J=3.6 Hz, 1H), 8.34 (s, 1H, NH), 8.42 (s, 1H, NH); ¹⁹FNMR (282 MHz, acetone-d ₆): δ- 168.06; LCMS: ret. time: 18.17 min.;purity: 97.47%; MS (m/e): 352.05 (MH⁺). 7.3.466N4-(4-Cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945172) In a manner analogous to the preparation ofN2,N4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N4-(4-aminocarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,trifluoroacetic anhydride and pyridine in THF gaveN4-(4-cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ4.27 (m, 4H), 4.82 (s, 2H), 6.70 (dd, J=2.4 and 8.4 Hz,1H), 6.75 (d, J=2.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 7.02 (d, J=9.0 Hz,2H), 7.32 (d, J=9.0 Hz, 2H), 8.64 (d, J=1.8 Hz, 1H); ¹⁹F NMR (282 MHz,CDCl₃): δ- 135.58; LCMS: ret. time: 19.92 min.; purity: 98.02%; MS(m/e): 393.98 (MH⁺). 7.3.467N2,N4-Bis[4-[2-methoxyimino(amino)ethyleneoxy]phenyl]-5-fluoro-2,4-pyrimidinediamine(R945096)N2,N4-Bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (50mg, 0.13 mmol), methoxyamine HCl salt (54 mg, 0.65 mmol) and sodiumbicarbonate (54 mg, 0.65 mmol) were dissolved in methanol (5 mL). Thereaction solution was stirred at 70° C. for 7 days. Then methanol wasremoved under reduced pressure. The residue was partitioned in EtOAc (60ml) and water (60 mL). The ethyl acetate layer was washed with water (2× 60 mL), dried, evaporated and purified by flash column chromatography(EtOAc/hexanes; 1:1; EtOAc) to giveN2,N4-bis[4-[2-methoxyimino(amino)ethyleneoxy]phenyl]-5-fluoro-2,4-pyrimidinediamine(30 mg, 48%). ¹H NMR (acetone-d ₆): δ3.70 (s, 3H), 3.71 (s, 3H), 4.44(s, 2H), 4.49 (s, 2H), 5.43 (br, 2H), 5.47 (br, 2H), 6.93 (d, J=9.0 Hz,2H), 7.00 (d, J=9.0 Hz, 2H), 7.62 (d, J=9.0 Hz, 2H), 7.71 (d, J=9.0 Hz,2H), 7.93 (d, J=3.6 Hz, 1H), 8.26 (br, 1H, NH), 8.40 (br, 1H, NH); ¹⁹FNMR (282 MHz, acetone-d ₆): δ- 169.08; LCMS: ret. time: 14.41 min.;purity: 100%; MS (m/e): 484.97 (MH⁺). 7.3.468N2-(4-Carboxymethyleneoxyphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945097) In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine,N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(10 mg, 0.024 mmol) and LiOH (2 mg, 0.048 mmol) gaveN2-(4-carboxymethyleneoxyphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(5 mg, 52%) as a white solid. ¹H NMR (CD₃OD): δ4.60 (s, 2H), 4.99 (s,2H), 6.88 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.7 Hz,2H), 7.65 (d, J=9.0 Hz, 2H), 7.84 (d, J=3.9 Hz, 1H); ¹⁹F NMR (282 MHz,CD₃OD): δ- 168.81; LCMS: ret. time: 17.95 min.; purity: 86.04%; MS(m/e): 409.99 (MH⁺). 7.3.4695-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945127) A mixture of 3-nitrophenol (4 g, 29 mmol), bromoacetonitrile(2.5 mL, 36 mmol) and K₂CO₃ (8 g, 58 mmol) in acetone (20 mL) wasstirred at room temperature overnight. The reaction mixture was dilutedwith water (80 mL) and acetone was removed under reduced pressure. Thelight-yellow precipitate was collected by filtration, washed with waterand dried to give 1-cyanomethyleneoxy-3-nitrobenzene.1-Cyanomethyleneoxy-3-nitrobenzene (2 g, 11 mmol) was dissolved inmethanol (20 mL) and to the solution was added hydroxyamine HCl salt (1g, 14 mmol) and triethylamine (3 mL, 22 mmol). The reaction mixture wasrefluxed for 2 h and the solvent was removed under reduced pressure. Theresidue was redissolved in THF (30 mL). To the solution was added acetylchloride (4 mL, 56 mmol) and pyridine (9 mL, 0.11 mol). The reactionmixture was stirred at room temperature overnight, then added THF (10mL), water (10 mL) and NaOH (3 g, 75 mmol). The reaction solution wasrefluxed overnight, diluted with water (80 mL). The aqueous solution wasextracted with EtOAc (3 × 60 mL). After separation, the combined EtOAclayers was dried, evaporated to give1-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxy-3-nitrobenzene.1-(5-Methyl-1,2,4-oxadiazol-3-yl)methyleneoxy-3-nitrobenzene wasdissolved in THF (10 mL) and water (10 mL) and to it were added sodiumbisulfite (1 g, 5.7 mmol) and sodium bicarbonate (1 g, 12 mmol). Theresulting mixture was stirred at room temperature for 30 min, thendiluted with EtOAc (80 mL) and water (80 mL). The aqueous solution wasextracted with EtOAc (80 mL). The organic layers were combined, dried,evaporated to give 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline(500 mg, 22% in four steps). The reaction of2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (40 mg, 0.17mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (102 mg,0.50 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(35mg, 51%). ¹H NMR (CDCl₃): δ2.61 (s, 3H), 5.09 (s, 2H), 6.58-6.62 (m,2H), 6.76 (dt, J=1.2, 8.1 Hz, 1H), 6.84 (dt, J=1.2 and 7.8 Hz, 1H), 6.92(d, J=3.0 Hz, 1H), 7.139 (t, J=8.1 Hz, 1H), 7.145 (t, J=8.1 Hz, 1H),7.25 (m, 1H), 7.54 (dt, J=2.1, 8.7 Hz, 2H), 7.88 (d, J=3.3 Hz, 1H); ¹⁹FNMR (282 MHz, CDCl₃): -166.52; LCMS: ret. time: 19.33 min.; purity:84.80%; MS (m/e): 409.35 (MH⁺). 7.3.4705-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945130) 1-Methoxycarbonylmethyleneoxy-3-nitrobenzene (2 g, 9.5 mmol)was dissolved in THF (10 mL) and water (10 mL). To the solution wasadded NaOH (1 g, 25 mmol). The reaction mixture was stirred at roomtemperature overnight. The solution was diluted with water (60 mL) andEtOAc (60 mL). After extraction, the aqueous layer was separated,acidified with 1N HCl to pH 3. The formed white precipitate wascollected by filtration, washed with water, dried to give1-carboxymethyleneoxy-3-nitrobenzene. Acetonitrile (2.25 mL, 43 mmol)was dissolved in methanol (10 mL) and to the solution was addedhydroxyamine HCl salt (2 g, 29 mmol) and triethylamine (8 mL, 57 mmol).The reaction mixture was refluxed for 2 days and the solvent was removedunder reduced pressure to give acetamide oxime as white solid. Acetamideoxime (0.75 g, 10 mmol), 1-carboxymethyleneoxy-3-nitrobenzene (1 g, 5mmol), EDC HCl (1.45 g, 7.5 mmol) and diisopropylethylamine (2.65 mL, 15mmol) were dissolved in THF (15 mL) and refluxed for 4h. The reactionmixture was diluted with EtOAc (60 mL) and water (60 mL). The EtOAclayer was washed with sodium bicarbonate aqueous solution (2 × 60 mL),1N HCl (2 × 60 mL) and water (60 mL). After separation, the EtOAc layerwas dried, evaporated to give1-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxy-3-nitrobenzene. Sodiumbisulfite (1.5 g, 8.6 mmol), sodium bicarbonate (1.5 g, 18 mmol) and1-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxy-3-nitrobenzene (1 g, 4mmol) were dissolved in THF (15 mL) and water (15 mL). It was stirred atroom temperature for 20 min, diluted with EtOAc (60 mL) and water (60mL). The aqueous solution was extracted with EtOAc (2 × 60 mL). Theorganic layers were combined, dried, evaporated to give3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyaniline. In a manneranalogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction of 3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyaniline(369 mg, 1.8 mmol) and 2,4-dichloro-5-fluoropyrimidine (150 mg, 0.9mmol) gave2-chloro-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine.The reaction of2-chloro-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine(20 mg, 0.06 mmol) and 3-hydroxyaniline (20 mg, 0.18 mmol) gave5-fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(10 mg, 42%). ¹H NMR (CDCl₃): δ2.42 (s, 3H), 5.28 (s, 2H), 6.49 (ddd,J=0.9, 2.7 and 8.4 Hz, 1H), 6.73 (ddd, J=0.9, 2.7 and 8.4 Hz, 1H),6.81-6.84 (m, 2H), 6.88 (ddd, J=0.6, 2.1 and 8.1 Hz, 1H), 7.13 (t, J=8.1Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 7.40 (br, 1H), 7.49 (t, J=2.1 Hz, 1H),7.94-7.97 (m, 2H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 167.11; LCMS: ret. time:18.80 min.; purity: 92.01%; MS (m/e): 409.01 (MH⁺). 7.3.4715-Fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945131) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,the reaction ofN4-(2-carboxybenzofuran-5-yl)-2-chloro-5-fluoro-4-pyrimidineamine (50mg, 0.16 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline(100 mg, 0.49 mmol) gaveN4-(2-carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.In a manner analogous to the preparation ofN2,N4-bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine,the reaction ofN4-(2-carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,potassium carbonate (100 mg, 0.7 mmol) and iodomethane (0.03 mL, 0.5mmol) gave5-fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(40 mg, 50%). ¹H NMR (acetone-d ₆): δ2.63 (s, 3H), 3.94 (s, 3H), 5.04(s, 2H), 6.65 (ddd, J=0.9, 2.4 and 7.8 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H),7.24 (ddd, J=1.2, 1.8 and 8.1 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.64 (d,J=9.3 Hz, 1H), 7.67 (t, J=2.1 Hz, 1H), 7.88 (dd, J=2.1 and 9.0 Hz, 1H),8.04 (d, J=3.6 Hz, 1H), 8.26 (d, J=1.8 Hz, 1H), 8.47 (br, 1H, NH), 8.71(br, 1H, NH); ¹⁹F NMR (282 MHz, acetone-d ₆): δ- 167.73; LCMS: ret.time: 22.55 min.; purity: 85.43%; MS (m/e): 490.97 (MH⁺). 7.3.472N4-(2-Carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945134) In a manner analogous to the preparation ofN2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof5-fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(20 mg, 0.04 mmol) and NaOH (10 mg, 0.25 mmol) gaveN4-(2-carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (acetone-d ₆): δ2.63 (s, 3H), 5.04 (s, 2H), 6.64 (d, J=8.1 Hz,1H), 7.17 (t, J=8.1 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.62(d, J=9.3 Hz, 1H), 7.67 (t, 1H), 7.86 (dd, J=1.8 and 9.0 Hz, 1H), 8.04(d, J=3.3 Hz, 1H), 8.26 (d, 1H), 8.48 (br, 1H, NH), 8.71 (br, 1H, NH);LCMS: ret. time: 18.00 min.; purity: 75.13%; MS (m/e): 476.70 (MH⁺).7.3.473N4-(2-Aminocarbonylbenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945135) A mixture of5-fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(20 mg, 0.04 mmol) and concentrated NH₄OH (5 mL) in methanol (5 mL) wasstirred at room temperature overnight. The solvent was evaporated togiveN4-[2-(aminocarbonyl)benzofuran-5-yl]-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (acetone-d ₆): δ2.61 (s, 3H), 5.04 (s, 2H), 6.64 (ddd, J=0.9, 2.4and 8.1 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 7.27 (ddd, J=0.9, 1.8 and 8.4Hz, 1H), 7.44 (d, J=0.6 Hz, 1H), 7.55 (dd, J=0.6 and 8.1 Hz, 1H), 7.64(t, J=2.4 Hz, 1H), 7.79 (dd, J=2.4 and 9.0 Hz, 1H), 8.03 (d, J=3.6 Hz,1H), 8.24 (d, J=2.4 Hz, 1H), 8.48 (br, 1H, NH), 8.68 (br, 1H, NH); ¹⁹FNMR (282 MHz, acetone-d ₆): δ- 167.80; LCMS: ret. time: 17.43 min.;purity: 100%; MS (m/e): 475.62 (MH⁺). 7.3.4745-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-methoxyimino(amino)ethyleneoxy)phenyl]-2,4-pyrimidinediamine(R945167) In a manner analogous to the preparation ofN2,N4-bis[4-(2-methoxyimino(amino)ethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine,the reaction ofN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(50 mg, 0.14 mmol), methoxyamine HCl salt (0.71 mmol) and triethylamine(0.2 mL, 1.4 mmol) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-methoxyimino(amino)ethyleneoxy)phenyl]-2,4-pyrimidinediamine(40 mg, 70%). ¹H NMR (CDCl₃): δ3.82 (s, 3H), 4.50 (s, 2H), 4.87 (br, 2H,NH), 6.60 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 6.79-6.84 (m, 2H), 6.86 (d,J=8.7 Hz, 2H), 7.00 (s, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.34 (d, J=9.0 Hz,2H), 7.47 (t, J=2.1 Hz, 1H), 7.87 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz,CDCl₃): δ- 167.67; LCMS: ret. time: 13.69 min.; purity: 92.51%; MS(m/e): 399.01 (MH⁺). 7.3.475N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-methoxyimino(amino)ethyleneoxyphenyl]-2,4-pyrimidinediamine(R945175) In a manner analogous to the preparation ofN2,N4-bis[4-(2-methoxyimino(amino)ethyleneoxyphenyl)]-5-fluoro-2,4-pyrimidinediamine,N4-(4-cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,methoxyamine hydrochloride salt and triethylamine gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-methoxyimino(amino)ethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ3.70 (s, 3H), 4.21-4.28 (m, 4H), 4.48 (s, 2H),5.46 (br, 2H), 6.71 (d, J=8.7 Hz, 1H), 6.99 (d, J=9.0 Hz, 2H), 7.06 (dd,J=2.4 and 8.7 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.72 (d, J=9.3 Hz, 2H),7.93 (d, J=3.3 Hz, 1H), 8.22 (br, 1H, NH), 8.40 (br, 1H, NH); ¹⁹F NMR(282 MHz, acetone-d₆): δ- 169.05; LCMS: ret. time: 16.49 min.; purity:96.47%; MS (m/e): 440.96 (MH⁺). 7.3.476N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926495) A mixture of N2-(3-ethoxy/ormethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(19.8 g, 45 mmol), methylamine hydrochloride (30.63 g, 450 mmol) anddiisopropylethylamine (78.07 mL, 450 mmol) in MeOH (450 mL) was stirredin a pressure bottle at 100° C. for 8 h (followed by TLC). The reactionwas cooled to room temperature, diluted with H₂O (6 lit), the solidobtained was filtered, washed with H₂O and dried to obtain 18 g ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxyphenyl)]-2,4-pyrimidinediamine.Alternatively, the reaction of equimolar amount of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-aminopyridine with3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h and or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.90 (s, 1H), 7.89 (bs, 1H), 7.38 (d, 1H, J=2.4 Hz),7.28 (d, 1H, J=2.4 Hz), 7.17-7.09 (m, 2H), 6.79 (d, 1H, J=9 Hz), 6.57(m, 1H), 4.38 (s, 2H), 4.24 (s, 4H), 2.81 (s, 3H); LCMS: ret. time:18.20 min.; purity: 98%; MS (m/e): 426 (MH⁺). 7.3.477N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R921219) In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.8 (d, 1H), 7.4 (m, 1H), 7.05 (m, 2H), 7.0 (s, 1H),6.8 (dd, 1H), 6.66 (d, 1H), 6.56 (dd, 1H), 4.35 (s, 2H), 4.18 (m, 2H),3.25 (m, 2H), 2.8 (s, 3H); LCMS: ret time: 18.0 min. purity: 97 %; MS(m/e): 425 (MH⁺). 7.3.478N4-(3,4-Ethylendioxyphenyl)-5-fluoro-N2-[4-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909239) In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 2-hydroxyethylamine were reacted to yieldN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[4-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine. ¹H NMR (D₂O): δ8.02(d, 1H, J=4 Hz), 7.40 (m, 2H), 7.28 (m, 1H), 7.05 (m, 5H), 4.83 (s, 2H),4.5 (m, 2H), 4.23 (m, 2H), 4.03(m, 2H), 3.87 (m, 2H); LCMS: ret. time:17.17 min.; purity: 94%; MS (m/e): 456 (MH⁺). 7.3.479N4-(3,4-Ethylendioxyphenyl)-5-fluoro-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909240) In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-(N-methylamino)carbonylmethyleneoxyaniline were reacted to yieldN4-(3,4-ethylendioxyphenyl)-5-fluoro-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (D₂O): δ8.02 (d, 1H, J=4 Hz), 7.40 (m, 2H), 7.28 (m, 1H), 7.05(m, 5H), 4.83 (s, 2H), 4.5 (m, 2H), 4.23 (m, 2H), 3.87 (s, 3H); LCMS:ret. time: 18.43 min.; purity: 94%; MS (m/e): 426 (MH⁺) 7.3.480N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-2-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909251) In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamineand 2-hydroxypropylamine were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-2-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ7.99 (d, 1H, J=4 Hz), 7.25 (m, 2H), 7.04 (m, 1H),6.82 (m, 2H), 6.58 (m, 1H), 6.45 (m, 1H) 4.36 (s, 2H), 4.02 (m, 2H),3.75 (m, 1H), 3.31 (m, 2H), 3.00 (m, 2H), 1.00 (m, 3H); LCMS: ret. time:17.33 min.; purity: 97 %; MS(m/e): 469 (MH⁺). 7.3.481N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-3-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909252) In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-[3-ethoxyocarbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineand 3-hydroxypropylamine were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-3-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ7.99 (d, 1H, J=4 Hz), 7.39 (m, 2H), 7.04 (m, 1H),6.87 (m, 2H), 6.55 (m, 1H), 6.41 (m, 1H), 4.29 (s, 2H), 4.02 (m, 2H),3.35 (m, 2H), 3.31 (m, 2H), 3.09 (m, 2H), 1.50 (m, 3H); LCMS: ret. time:17.11 min.; purity: 94 %; MS (m/e): 469 (MH⁺). 7.3.482N4-(1,4-Benzoxazin-6-yl)-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R909254) In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)]-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-pyrimidinediamineand isopropylamine were reacted to yieldN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ7.79 (d, 1H, J=4 Hz), 7.25 (m, 1H), 7.14 (m, 1H),7.02 (m, 1H), 6.85 (m, 3H), 6.63 (m, 1H), 4.39 (s, 2H), 4.12 (m, 2H),4.05 (m, 1H), 3.38 (m, 2H), 1.20 (m, 6H); LCMS: ret. time: 20.83 min.;purity: 96 %; MS (m/e): 453 (MH⁺). 7.3.4835-Fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(N-pyrrolidino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926703) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineand pyrrolidine were reacted to yield5-fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(N-pyrrolidino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.83 (s, 1H), 7.79 (d, 1H, J=5.4 Hz), 7.42 (bs, 1H),7.39 (d, 2H, J=8.7 Hz), 7.28-7.24 (m, 2H), 6.81 (d, 2H, J=8.7 Hz), 4.52(2q, 1H, J=6.0 Hz), 3.92 (t, 2H, J=6.9 Hz), 3.67 (t, 2H, J=6.9 Hz),2.05-1.90 (m, 4H), 1.32 (d, 6H, J=6.6 Hz); ¹⁹F NMR (CDCl₃): - 24000;LCMS: ret. time: 23.49 min.; purity: 97 %; MS (m/e): 476 (MH⁺). 7.3.484N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926708) In a manner similar to the preparation ofN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.10 (bs, 1H), 9.88 (bs, 1H), 8.15 (t, 1H, J=4.5Hz), 8.05 (bs, 1H), 7.40 (d, 2H, J=8.7 Hz), 7.23 (d, 1H, J=2.1 Hz), 7.11(dd, 1H, J=2.4 and 8.7 Hz), 6.89 (d, 2H, J=8.7 Hz), 6.81 (d, 1H, J=8.7Hz), 4.42 (s, 2H), 4.23 (s, 4H), 2.64 (d, 3H, J=4.5 Hz); LCMS: ret.time: 17.60 min.; purity: 96 %; MS (m/e): 426 (MH⁺). 7.3.485N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926494) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN4-(4-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.04 (d, 1H, J=2.4 Hz), 7.88 (d, 1H, 4.2 Hz), 7.58-7.30(m, 7H), 2.94 (s, 3H), 1.33 (s, 9H); LCMS: ret. time: 22.86 min.;purity: 94%; MS (m/e): 434 (MH⁺). 7.3.486N4-(4-tert-Butylphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926712) In a manner similar to the preparation ofN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[4-(tert-butyl)phenyl]-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.92 (d, 1H, J=5.4 Hz), 7.53 (d, 2H, J=8.7 Hz), 7.40(d, 2H, J=8.7 Hz), 7.34 (d, 2H, J=8.7 Hz), 7.03 (d, 2H, J=8.7 Hz), 4.52(s, 2H), 2.82 (s, 3H), 1.35 (s, 9H); ¹⁹F NMR (CD₃OD): - 46174; LCMS:ret. time: 23.34 min.; purity: 94 %; MS (m/e): 424 (MH⁺). 7.3.487N4-(3-tert-Buthylpheny)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineR940295 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 2-hydroxyethylamine were reacted to giveN4-(3-tert-butylpheny)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 21.34 min.; purity: 97 %; MS (m/e): 453 (M⁺); 454(MH⁺); ¹H NMR (CDCl₃): δ10.34 (1H, s), 7.76 (1H, m), 7.52 (1H, m),7.4-7.1 (5H, m), 6.98 (1H, m), 6.7 (1H, m), 4.36 (2H, s), 3.77 (2H, t, J5 Hz), 3.51 (2H, m), 1.27 (9H, s). 7.3.488N2,N4-Bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926562) In like manner of the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediaminewith pyrrolidine gaveN2,N4-bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.17 (s, 1H), 8.73 (bs, 1H), 7.50(bd, 2H, J=9.0 Hz),7.43 (d, 2H, J=2.4 and 6.9 Hz), 6.91 (m, 4H), 4.64 (s, 2H), 4.62 (s,2H), 4.34 (q, 2H, J=7.2 Hz), 3.53 (m, 8H), 1.95 (m, 4H), 1.86 (m, 4H),1.38 (t, 3H, J=6.9 Hz); LCMS: ret. time: 22.54 min.; purity: 100%; MS(m/e): 590 (MH⁺). 7.3.489N2,N4-Bis(4-N-pyrrolidinocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926563) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith pyrrolidine gaveN2,N4-bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.90 (s, 1H), 7.50 (bd, 2H, J=7.8 Hz), 7.41 (bd, 2H,J=7.2 Hz), 6.93 (m, 4H), 6.73 (s, 1H), 6.64 (s, 1H), 4.65 (s, 1H), 4.65(s, 1H), 3.54 (m, 8H), 1.96 (m, 4H), 1.87 (m, 4H). 7.3.490N4-(3-tert-Butylpheny)-N2-[3-(N-1,3-dihydroxypropyl-2-amino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R940296) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand 2-amino-1,3-propanediol were reacted to giveN4-(3-tert-butylpheny)-N2-[-3-(1,3-dihydroxypropyl-2-amino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 20.26 min.; purity: 97.67 %; MS (m/e): 484 (M⁺); 485(MH⁺); 1H NMR (DMSO-d₆): δ9.75 (1H, s), 9.57 (1H, s), 8.25 (1H, m), 7.92(1H, m), 7.62 (2H, m), 7.37 (3H, m), 7.23 (1H, m), 6.66 (1H, m), 4.46(2H, s), 3.87 (1H, m), 3.55 (4H, m), 1.36 (9H, s). 7.3.491N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamineR940290 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted to giveN2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 20.04 min.; purity: 98 %; MS (m/e): 470 (MH⁺); ¹H NMR(DMSO-d₆): δ9.54 (1H, s), 9.41 (1H, s), 8.22 (1H, m), 7.95 (1H, m), 7.85(1H, d, J=10 Hz), 7.58 (1H, s), 7.43-7.32 (3H, m), 7.25 (1H, t, J=7.75Hz), 7.06 (1H, d, J=7.75 Hz), 6.64 (1H, d, J=10 Hz), 4.47 (2H, s), 3.38(4H, m), 3.16 (1H, m), 2.96 (1H, m), 1.28 (6H, d, J=6.9 Hz). 7.3.4925-Fluoro-N4-(3-isopropylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineR940288 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to give5-fluoro-N4-(3-isopropylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 23.43 min.; purity: 99 %; MS (m/e): 409 (M⁺), 411(MH⁺); ¹H NMR (DMSO-d₆): δ9.90 (1H, s), 9.74 (1H, s), 8.28 (1H, d, J=4.8Hz), 8.06 (1H, m), 7.78 (1H, d, J=7.2 Hz), 7.58 (1H, s), 7.4-7.3 (3H,m), 7.24 (1H, t, J=8.4 Hz), 7.00 (1H, d, J=7.25 Hz), 6.70 (1H, d, J=7.25Hz), 4.44 (2H, s), 2.93 (1H, sept, J=6.9 Hz), 2.74 (3H, d, J=4.8 Hz),1.27 (6H, d, J=6.9 Hz). 7.3.4935-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-dimethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926718) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand dimethylamine were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-dimethylamino)carbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.06 (d, 1H, J=2.1 Hz), 7.91 (d, 1H, J=3.6 Hz), 7.57(t, 1H, J=2.4 Hz), 7.37 (d, 1H, J=9.0 Hz), 7.28 (s, 1H), 7.19 (t, 1H,J=7.8), 7.06 (s, 1H), 6.82-6.76 (m, 2H), 6.71 (dd, 1H, J=2.4 and 7.8Hz), 3.31 (s, 3H), 3.09 (s, 3H); ¹⁹F NMR (CDCl₃): - 47292; LCMS: ret.time: 17.29 min.; purity: 92 %; MS (m/e): 408 (MH⁺). 7.3.494N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945149) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(700 mg, 1.6 mmol) and piperazine (4 g, 46 mmol) gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(520 mg, 66%). ¹H NMR (CD₃OD): δδ2.22 (s, 3H), 2.75 (t, J=5.4 Hz, 4H),3.40 (t, J=4.8 Hz, 2H), 3.54 (t, J=5.1 Hz, 2H), 4.62 (s, 2H), 6.57 (ddd,J=1.5, 2.7 and 7.5 Hz, 1H), 7.09 (dt, J=1.5 and 8.1 Hz, 1H), 7.14 (t,J=7.8 Hz, 1H), 7.28 (t, J=2.1 Hz, 1H), 7.31 (dd, J=0.9 and 2.7 Hz, 1H),7.50 (d, J=2.7 Hz, 1H), 7.88 (d, J=3.9 Hz, 1H); ¹⁹F NMR (282 MHz,CD₃OD): δ- 168.63; LCMS: ret. time: 14.99 min.; 93.88%; MS (m/e): 486.96(MH⁺). 7.3.495N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine (R926713) In a manner similar to the preparationofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylaminocarbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.05 (d, 1H, J=2.4 Hz), 7.88 (d, 1H, J=4.2 Hz), 7.57(d, 2H, J=8.7 Hz), 7.51-7.41 (m, 2H), 7.34-7.31 (m, 3H), 2.94 (s, 3H),1.33 (s, 9H); ¹⁹F NMR (CD₃OD): - 47682; LCMS: ret. time: 23.02 min.;purity: 90 %; MS (m/e): 434 (MH⁺). 7.3496N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926796) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethoxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyridinediaminewith methylamine hydrochloride gaveN4-(3,5-dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.92 (d, 1H, J=4.2 Hz), 7.42 (t, 1H, J=1.8 Hz), 7.12(m, 2H), 6.91 (d, 1H, J=2.4 Hz), 6.59 (m, 1H), 6.22 (t, 1H, J=1.8 Hz),4.35 (s, 2H), 3.69 (s, 6H), 2.81 (s, 3H); LCMS: ret. time: 18.35 min.;purity: 93%; MS (m/e): 428 (MH⁺). 7.3.4975-Ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926800) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-2,4-pyridinediaminewith methylamine hydrochloride gave5-ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.05 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 7.95 (d,1H, J=4.8 Hz), 7.34 (dd, 1H, J=1.2 and 7.8 Hz), 7.25 (bs, 2H), 7.13 (t,1H, J=8.1 Hz), 7.00 (bd, 1H, J=9Hz), 6.81 (d, 1H, J=8.7 Hz), 6.59 (dd,1H, J=1.5 and 8.4 Hz), 4.32 (s, 2H), 4.30 (q, 2H, J=7.2 Hz), 4.21 (s,4H), 2.63 and 2.62 (2s, 3H), 1.31 (t, 3H, J=7.2 Hz); LCMS: ret. time:24.12 min.; purity: 91%; MS (m/e): 481 (MH⁺). 7.3.498N4-(3,5-Dimethoxyphenyl)-5-ethoxycarbonyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926801) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxyphenyl)]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethoxyphenyl)-5-ethoxycarbonyl-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediaminewith methylamine hydrochloride gaveN4-(3,5-dimethoxyphenyl)-5-ethoxycarbonyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.20 (s, 1H), 9.96 (s, 1H), 8.73 (s, 1H), 7.90 (bs,1H), 7.36 (d, 1H, J=8.7 Hz), 7.28 (bs, 1H), 7.12 (t, 1H, J=7.5 Hz), 6.84(s, 2H), 6.59 (dd, 1H, J=1.8 and 8.1 Hz), 6.25 (t, 1H, J=2.4 Hz), 4.31(m, 4H), 3.67 (s, 6H), 2.63 and 2.62 (2s, 3H), 1.31 (t, 3H, J=7.2 Hz);LCMS: ret. time: 25.50 min.; purity: 96%; MS (m/e): 482 (MH⁺). 7.3.499N4-(4-tert-Butylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926714) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(4-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹HNMR (CD₃OD): δ7.90 (d, 1H, J=3.3 Hz), 7.61 (d, 2H, J=8.7 Hz), 7.40-7.33(m, 3H), 7.14-7.11 (m, 2H), 6.62-6.57 (m, 1H), 4.36 (s, 2H), 2.79 (s,3H), 1.31 (s, 9H); ¹⁹F NMR (CD₃OD): - 47514; LCMS: ret. time: 23.70min.; purity: 93 %; MS (m/e): 424 (MH⁺). 7.3.500N4-(3-Hydroxyphenyl)-5-trifluoromethyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926742) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-hydroxyphenyl)-5-trifluoromethyl-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3-hydroxyphenyl)-5-trifluoromethyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 19.11 min.; purity: 99 %; MS (m/e): 434 (MH⁺). 7.3.5015-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926745) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)-indol-6-yl]-4-pyrimidineamine and3-(N-methylamino)carbonylmethyleneoxyaniline were reacted to yield5-fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 17.41 min.; purity: 93 %; MS (m/e): 407(MH⁺). 7.3.502N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945156) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and piperazine gaveN4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ2.23 (s, 6H), 3.24 (m, 4H), 3.71 (s, 3H), 3.72-3.81 (m,4H), 4.75 (s, 2H), 6.81 (dt, J=1.2 and 8.1 Hz, 1H), 7.10-7.13 (m, 2H),7.24 (d, J=8.7 Hz, 1 H), 7.29 (s, 2H), 7.98 (d, J=4.8 Hz, 1H); ¹⁹F NMR(282 MHz, CD₃OD): δ- 163.88; LCMS: ret. time: 15.94 min.; purity: 100%;MS (m/e): 481.12 (MH⁺). 7.3.503N4-(3-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofur-5-yl]-2,4-pyrimidinediamineR940291 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to giveN4-(3-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofur-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 23.05 min.; purity: 100 %; MS (m/e): 434 (MH⁺); ¹H NMP(DMSO-d₆): δ9.6 (1H, s), 9.57 (1H, s), 8.75 (1H, m), 8.25 (1H, s), 8.15(1H, s), 7.93 (1H, d, J=8.5 Hz), 7.47 (3H, m), 7.44 (1H, s), 7.36 (1H,t, J=8.5 Hz), 7.25 (1H, d, J=8.5 Hz), 2.89 (3H, d, J=4.5 Hz), 1.33 (9H,s). 7.3.504N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926505) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxy)phenyl)-2,4-pyrimidinediamineand 2-hydroxyethylamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.87 (d, 1H, J=3.6 Hz), 7.37 (t, 1H, J=1.8 Hz), 7.24(d, 1H, J=2.4 Hz), 7.13 (m, 2H), 7.08 (dd, 1H, J=2.1 and 8.1 Hz), 6.77(m, 1H), 4.38 (s, 2H), 4,22 (s, 3H), 3.63 (t, 2H), 3.40 (t, 2H, J=6 Hz);LCMS: ret. time: 16.72 min.; purity: 98%; MS (m/e): 456 (MH⁺). 7.3.5055-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926746) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.84 min.; purity: 96 %; MS (m/e): 444 (MH⁺). 7.3.5065-Fluoro-N2-[2-(2-hydroxy-1,1-dimethylethylamino)carbonylbenzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926715) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand 2-amino-2-methylpropanol were reacted to yield5-fluoro-N2-[2-(2-hydroxy-1,1-dimethylethylamino)carbonylbenzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.41 (s, 1H), 9.28 (s, 1H), 9.22 (s, 1H), 8.18 (t,1H, J=2.4, Hz), 8.09 (d, 1H, J=3.6 Hz), 7.56 (dd, 1H, J=2.4 and 8.7 Hz),7.47 (d, 1H, J=8.7 Hz), 7.32 (s, 1H), 7.26-7.21 (m, 1H), 7.13- 7.07 (m,2H), 6.53 (d, 1H, J=8.7 Hz), 5.05 (t, 1H, J=5.7 Hz), 3.46 (d, 2H, J=5.7Hz), 1.32 (s, 6H); LCMS: ret. time: 17.93 min.; purity: 97 %; MS (m/e):452 (MH⁺). 7.3.5075-Fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926730) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yield5-fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.93 (d, 1H, J=3.0 Hz), 7.47 (d, 2H, J=9.3 Hz), 7.42(t, 1H, J=1.8 Hz), 7.17 (t, 1H, J=8.1 Hz), 7.10 (bs, 1H), 7.00 (dd, 1H,J=1.8 and 9.3 Hz), 6.89 (d, 2H, J=9.3 Hz), 6.80 (d, 1H, J=1.8 Hz), 6.58(bs, 1H), 6.50 (dd, 1H, J=1.5 and 8.1 Hz), 4.51 (2q, 1H, J=5.7 Hz), 4.44(s, 2H), 2.88 (d, 3H, J=4.5 Hz), 1.33 (d, 6H, J=5.7 Hz); ¹⁹F NMR(CDCl₃): - 47198; LCMS: ret. time: 19.66 min.; purity: 97 %; MS (m/e):426 (MH⁺). 7.3.5085-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945170) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)methyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ2.91 (d, J=5.1 Hz, 3H), 4.48 (s, 2H), 6.61 (ddd, J=0.9,2.7 and 8.1 Hz, 1H), 6.63 (br, 1H), 6.76 (d, J=3.0 Hz, 1H), 6.84-6.89(m, 4H), 7.18 (t, J=8.1 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.51 (t, J=2.1Hz, 1H), 7.92 (d, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ-167.70; LCMS: ret.time: 14.32 min.; purity: 100%; MS (m/e): 383.98 (MH⁺). 7.3.5095-Fluoro-N4-(3-isopropoxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926489) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-isopropoxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidineaminewith morpholine gave5-fluoro-N4-(3-isopropoxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.01 (d, 1H, J=1.2 Hz), 7.95 (bs, 1H), 7.43-7.38 (m,2H), 7.29 (s, 1H), 7.25-7.11 (m, 4H), 6.97 (bs, 1H), 6.73 (m, 1H), 6.67(bdd, 1H), 4.48 (sept, 1H, J=5.7 Hz), 3.87 (m, 4H), 3.79 (m, 4H), 1.30(d, 6H, J=5.7 Hz), LCMS: ret. time: 22.12 min.; purity: 98%; MS (m/e):492 (MH⁺). 7.3.5105-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926772) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith piperazine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.91 (d, 1H, J=3.6 Hz), 7.42 (t, 1H, J=2.4 Hz),7.20-7.07 (m, 5H), 6.55 (m, 2H), 4.63 (s, 2H), 3.54 (t, 2H, J=6 Hz),3.40 (t, 2H, J=5.1 Hz), 2.76 (t, 4H, J=5.4 Hz); LCMS: ret. time: 12.98min.; purity: 92%; MS (m/e): 439 (MH⁺). 7.3.5115-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926506) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith 2-hydroxyethylamine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 14.95 min.; purity: 96%; MS (m/e): 414 (MH⁺). 7.3.5125-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926508) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-ethoxy ormethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine withmethylamine hydrochloride gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.64 (bs, 1H), 9.58 (bs, 1H), 8.15 (d, 1H, J=4.2 Hz),7.95 (bd, 1H), 7.25 (bd, 2H, J=6.6 Hz), 7.16-7.07 (m, 4H), 6.53 (m, 2H),4.35 (s, 2H), 2.64 and 2.62 (2s, 3H); LCMS: ret. time: 15.66 min.;purity: 98%; MS (m/e): 384 (MH⁺). 7.3.5135-Fluoro-N4-[3,4-(1,1,2,2-tetrafluoroethylendioxy)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926732) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[3,4-(1,1,2,2-tetrafluoroethylendioxy)phenyl]-4-pyrimidineamineand methylamine hydrochloride were reacted to yield5-fluoro-N4-[3,4-(1,1,2,2-tetrafluoroethylendioxy)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ9.65 (s, 1H), 9.37 (s, 1H), 8.16 (d, 1H, J=3.6 Hz),8.14 (d, 1H, J=2.4 Hz), 7.97 (d, 1H, J=4.8 Hz), 7.65 ( dd, 1H, J=2.4 and8.7 Hz), 7.41 (d, 1H, J=9.3 Hz), 7.34 (t, 1H, J=2.4 Hz), 7.27 (d, 1H,J=8.1 Hz), 7.13 (t, 1H, J=8.1 Hz), 6.51 (dd, 1H, J=2.1 and 7.5 Hz), 4.36(s, 2H), 2.63 (d, 3H, J=4.8 Hz); ¹⁹F NMR (DMSO-d₆): - 25765 (pent,2F), - 25830 (pent, 2F), - 46309; LCMS: ret. time: 24.85 min.; purity:95 %; MS (m/e): 497 (MH⁺). 7.3.514N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R940254) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethyl-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith morpholine gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(N-morpholinocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.38 min.; purity: 92 %; MS (m/e): 468 (MH⁺); 1H NMR(DMSO-d₆): δ9.20 (1H, s), 9.10 (1H, s), 8.15 (1H, s), 8.11 (1H, d, J=3.9Hz), 7.43 (1H, d, J=8.1 Hz), 7.32 (3H, m), 7.14 (1H, t, J=8.1 Hz), 6.54(1H, dd, J=8.1 and 2.0 Hz), 4.77 (2H, s), 3.64 (4H, m), 3.54-3.45 (4H,m), 2.24 (6H, s). 7.3.515N4-(3-tert-Butylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R940276) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-tert-butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN4-(3-tert-butylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.90 min.; purity: 99 %; MS (m/e): 424 (MH⁺); 1H NMR(DMSO-d₆): δ9.46 (1H, s), 9.34 (1H, s), 8.08 (1H, d, J=3.9 Hz), 7.90(1H, m), 7.30 (1H, d, J=8.1 Hz), 7.46 (1H, m), 7.26 (1H, m), 7.20 (2H,m), 7.10-7.03 (2H, m), 6.47 (1H, d, J=8.1 Hz), 4.26 (2H, s), 2.59 (3H,d, J=4.5 Hz), 1.20 (9H, s). 7.3.516N4-(3-tert-Butylphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R940277) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-tert-butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith 2,3-dihydroxypropylamine gaveN4-(3-tert-butylphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: retn. time: 20.46 min.; purity: 100 %; MS (m/e): 484 (MH⁺); 1H NMR(DMSO-d₆): δ9.38 (1H, s), 9.29 (1H, s), 8.20 (1H, d, J=3.9 Hz), 8.00(1H, d, J=8.3 Hz), 7.93 (1H, t, J=5.5 Hz), 7.60 (1H, m), 7.47 (1H, m),7.41-7.17 (4H, m), 6.59 (1H, dd, J=8.3 and 2 Hz), 3.43 (2H, s), 3.39(4H, m), 3.16 (1H, m), 1.36 (9H, s). 7.3.517N4-(3,3-Dihydroisobenzofuran-1-one-6-yl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineR940293 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[3-(ethoxycarbonylmethyleneoxy)phenyl]-N4-(3,3-dihydroisobenzofuran-1-one-6-yl)-5-fluoro-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted toN4-(3,3-dihydroisobenzofuran-1-one-6-yl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.92 min.; purity: 92 %; MS (m/e): 483 (M⁺); 1H NMR(DMSO-d₆): δ9.80 (1H, s), 9.46 (1H, s), 8.37-8.27 (2H, m), 8.21 (1H, s),7.96 (1H, t, J=4.6Hz), 7.24 (1H, d, J=9Hz), 7.44 (1H, s), 7.37 (1H, d,J=9 Hz), 7.23 (1H, t, J=8 Hz), 6.60 (1H, dd, J=7 and 3.75 Hz) 5.49 (2H,s), 4.46 (2H, s), 3.38 (4H, m), 3.2-3.1 (1H, m). 7.3.518N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926733) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3,4-dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.95 (d, 1H, J=3.6 Hz), 7.45 (t, 1H, J=1.8 Hz),7.21-7.17 (m, 2H), 7.05 (dd, 1H, J=2.7 and 8.7 Hz), 6.96-6.90 (m, 2H),6.87 (d, 1H, J=9.0 Hz), 6.72 (d, 1H, J=2.4 Hz), 6.67-6.58 (m, 1H), 6.52(dd, 1H, J=3.6 and 8.1 Hz), 4.39 (s, 2H), 3.89 (s, 3H), 3.78 (s, 3H),2.90 (d, 3H, J=4.8 Hz); LCMS: ret. time: 17.09 min.; purity: 98 %; MS(m/e): 428 (MH⁺). 7.3.519 N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926734) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted to yieldN2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.05 (d, 1H, J=4.2 Hz), 7.38-7.34 (m, 2H), 7.31-7.26(m, 2H), 7.07 (t, 1H, J=8.4 Hz), 6.89 (d, 1H, J=8.7 Hz), 6.46 (dd, 1H,J=2.4 and 8.4 Hz), 4.36 (s, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 3.32-3.24(m, 3H), 3.03 (dd, 1H, J=6.9 and 13.5 Hz); ¹⁹F NMR (DMSO-d₆): - 46574;LCMS: ret. time: 14.85 min.; purity: 94 %; MS (m/e): 488 (MH⁺). 7.3.5205-Fluoro-N4-(3-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926738) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-methoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yield5-fluoro-N4-(3-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.40 min.; purity: 98 %; MS (m/e): 398 (MH⁺). 7.3.521N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-methoxyphenyl)-2,4-pyrimidinediamine(R926739) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-N4-(3-methoxyphenyl)-2,4-pyrimidinediamineand 3-amino-1,2-propanediol were reacted to yieldN2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-methoxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 16.66 min.; purity: 99 %; MS (m/e): 458 (MH⁺). 7.3.522N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945140) In a manner analogous to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and piperazine gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ2.18 (s, 6H), 2.72 (q, J=5.1 Hz, 4H), 3.32 (t, 2H),3.52 (t, J=5.1 Hz, 2H), 4.55 (s, 2H), 6.56 (ddd, J=1.2, 2.4 and 8.1 Hz,1 H), 7.03 (ddd, J=1.2, 1.8 and 8.1 Hz, 1H), 7.11 (t, J=8.1 Hz, 1H),7.20 (s, 2H), 7.35 (t, J=2.1 Hz, 1H), 7.84 (d, J=3.9 Hz, 1H); ¹⁹F NMR(282 MHz, CD₃OD): δ- 168.78; LCMS: ret. time: 14.32 min.; purity:88.37%; MS (m/e): 467.06 (MH⁺). 7.3.5235-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926488) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith morpholine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.19 (t, 1H, J=1.5 Hz), 7.90 (d, 1H, J=3.9 Hz), 7.44(d, 2H, J=0.9 hz), 7.28 (s, 1H), 7.21 (t, 1H, J=2.4 Hz), 7.15 (t, 1H,J=7.5 Hz), 7.08 (m, 1H), 7.61 (bd, 1H, J=6.9 Hz), 3.8 (m, 4H), 3.65 (m,4H); LCMS: ret. time: 17.21 min.; purity: 83%; MS (m/e): 450 (MH⁺).7.3.5245-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926493) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith methylamine hydrochloride gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.71 (d, 1H, J=4.8 Hz), 8.00-7.92 (m, 2H), 7.56-7.52(m, 1H), 7.44-7.39 (m, 2H), 7.12 (m, 2H), 6.69 (bdd, 1H), 2.96 and 2.94(2s, 3H). 7.3.5255-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926497) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith 2-hydroxyethylamine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.18 (d, 1H, J=1.8 Hz), 7.80 (bs, 1H), 7.60 (m, 1H),7.34-7.16 (m, 3H), 7.10 9t, 1H, 8.4 Hz), 6.85 (bdd, 1H), 6.62 (dd, 1H,J=1.5 and 8.1 Hz), 3.70 (t, 2H, J=4.8 Hz), 3.52 (t, 2H, J=4.0 Hz); LCMS:ret. time: 14.49 min.; purity: 97%; MS (m/e): 424 (MH⁺). 7.3.5265-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926500) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith piperazine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.19 (t, 1H, J=1.2 Hz), 7.90 (d, 1H, J=3.9 Hz), 7.43(d, 2H, J=1.2 Hz), 7.25-7.06 (m, 4H), 6.59 (m, 1H), 3.80 (m, 4H), 2.95(m, 4H); LCMS: ret. time: 12.97 min.; purity: 79%; MS (m/e): 449 (MH⁺).7.3.5275-Cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925844) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-N-methylaminocarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-cyano-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith methylamine hydrochloride gave5-cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.83 min.; purity: 96 %; MS (m/e): 391 (MH⁺). 7.3.5285-Cyano-N4-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925845) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-cyano-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminereacted with cyclopropylmethylamine to give5-cyano-N4-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 22.47 min.; purity: 100 %; MS (m/e): 431 (MH⁺). 7.3.5295-Cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925846) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-cyano-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminereacted with 2,3-dihydroxypropylamine to give5-cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 15.84 min.; purity: 100 %; MS (m/e): 451 (MH⁺). 7.3.5305-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethylphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-trifluoromethylphenyl)-2,4-pyrimidineaminewith methylamine hydrochloride gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)]-N4-(3-trifluoromethylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 21.98 min., purity: 86%, MS (m/e): 436 (MH⁺). 7.3.531N4-[4-(4,5-Dichloro-1H-imidazol-1-ylphenyl)]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926812) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN-4-[4-(4,5-dichloro-1H-imidazol-1-ylphenyl)]-5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine with methylamine hydrochloride gaveN4-[4-(4,5-dichloro-1H-imidazol-1-ylphenyl)]-5-fluoroN2-(3-[N-methylamino)carbonylmethylene oxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 21.02 min., purity: 100%, MS (m/e): 502 (MH⁺). 7.3.532N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylaminocarbonyllindol-7-yl)-2,4-pyridinediamine (R926815) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-trifluorophenyl)-2,4-pyrimidineaminewith methylamine hydrochloride gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylaminocarbonyllindol-7-yl)-2,4-pyridinediamine. LCMS: ret. time: 17.97 min., purity: 97%, MS (m/e):435 (MH⁺). 7.3.533N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926484) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand morpholine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.94 (bs, 1H), 7.35 (t, 1H, J=2.4 Hz), 7.24 (m, 1H),7.19 (t, 1H, J=8.1 Hz), 7.10 (bdd, 1H, J=6.9 Hz), 6.95 (m, 2H), 6.85 (d,1H, J=8.1 Hz), 6.94 (s, 1H), 6.58 (dd, 1H, J=1.8 and 2.8 Hz), 4.64 (s,2H), 4.27 9s, 4H), 3.62 (m, 4H), 3.55 (m, 4H); LCMS: ret. time: 18.45min.; purity: 100%; MS (m/e): 482 (MH⁺). 7.3.534N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926492) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuron-5-yl)-2,4-pyrimidinediaminewith morpholine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholino)carbonylbenzofuron-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.27 (s, 1H), 9.17 (s, 1H), 8.14 (d, 1H, J=2.4 Hz),8.05 (d, 1H, J=5.6 Hz), 7.58-7.46 (m, 2H), 7.27 (m, 1H), 7.15 (dd, 1H,J=2.4 and 9 Hz), 6.80 9m, 1H), 4.24 (s, 4H), 3.80-3.45 (m, 8H); LCMS:ret. time: 19.97 min.; purity: 76%; MS (m/e): 492 (MH⁺). 7.3.535N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926496) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand methylamine hydrochloride gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.06 (s, 1H), 7.85 (d, 1H, J=3.3 Hz), 7.42 (d, 2H,J=1.2 Hz), 7.35 (s, 1H), 7.29 (d, 1H, J=2.4 Hz). 6.99 (dd, 1H, J=3.3 and8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.24 (s, 4H), 2.94 (s, 3H); LCMS: ret.time: 18.05 min.; purity: 99%; MS (m/e): 436 (MH⁺). 7.3.536N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926498) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith 2-hydroxyethylamine yieldedN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.07 (d, 1H, J=1.2 Hz), 7.86 (d, 1H, J=3.9 Hz), 7.43(d, 2H, J=1.5 Hz), 7.38 (s, 1H), 7.29 (d, 1H, J=2.4 Hz). 6.98 (dd, 1H,J=2.1 and 9 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.23 (s, 4H), 3.72 (t, 2H,J=5.7 Hz), 3.53 (t, 2H, J=6.0 Hz); LCMS: ret. time: 16.21 min.; purity:97%; MS (m/e): 466 (MH⁺). 7.3.537N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926499) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand piperazine yieldedN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.26 (s, 1H), 9.16 (s, 1H), 8.12 (d, 1H, J=1.8 Hz),8.04 (d, 1H, J=3.6 Hz), 7.49 (d, 2H), 7.30 (d, 1H, J=2.4 Hz), 7.20 (s,1H), 7.15 (bdd, 1H, J=3 Hz), 6.79 (d, 1H, J=8.7 Hz), 4.22 (s, 4H), 2.48(s, 3H); LCMS: ret. time: 14.61 min.; purity: 94%; MS (m/e): 491 (MH⁺).7.3.538N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926503) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonymethyleneoxyphenyl)-2,4-pyrimidinediamineand piperazine were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ9.14 (bs, 2H), 8.04 (d, 3.6 Hz), 7.32-7.20 (m, 4H),7.06 (t, 1H, J=8.1 Hz), 6.79 (d, d, 1H, J=9 Hz), 6.43 (bd, 1H, J=9.9Hz), 4.64 (s, 2H), 4.20 (bs, 4H), 3.29 (m, 4H), 2.59 (m, 4H); LCMS: ret.time: 14.92 min.; purity: 99%; MS (m/e): 481 (MH⁺). 7.3.539N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxy-1,1-dimethylethylamino)carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine(R926764) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 2-amino-2-methylpropanol gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxy-1,1-dimethylethylamino)carboxymethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.95 (d, 1H, J=2.7 Hz), 7.47 (t, 1H, J=2.4 Hz), 7.20(t, 1H, J=8.1 Hz), 7.03 (dd, 1H, J=1.2 and 8.1 Hz), 6.98 (dd, 1H, J=3and 8.2 Hz), 6.93 (s, 1H), 6.84 (d, 1H, J=8.7 Hz), 6.66 (d, 1H, J=3 Hz),6.57 (bs, 1H), 6.53 (m, 1H), 4.65 (m, 1H), 4.39 (s, 2H), 4.28 (s, 4H),3.63 (d, 2H, J=5.7 Hz), 1.31 (s, 6H); LCMS: ret. time: 19.19 min.;purity: 89%; MS (m/e): 484 (MH⁺). 7.3.540N2-[3-(N-Cyclohexylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926765) In like manner to thepreparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand cyclohexylamine gave N2-[3-(N-cyclohexylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.94 (d, 1H, J=3.3 Hz), 7.41 (t, 1H, J=2.4 Hz), 7.28(d, 1H, J=2.4 Hz), 7.20 (t, 1H, J=7.5 Hz), 7.04 (dd, 1H, J=1.2 and 8.1Hz), 6.95 (m, 2H), 6.85 (d, 1H, J=8.7 Hz), 6.68 (d, 1H, J=3.0 Hz), 6.53(dd, 1H, J=2.4 and 8.4 Hz), 6.45 (bd, 1H, J=8.1 Hz), 4.43 (s, 2H), 4.24(s, 4H), 3.85 (m, 1H), 1.90 (m, 2H), 1.75-1.55 (m, 2H), 1.45-1.05 (m,6H); LCMS: ret. time: 23.70 min.; purity: 97%; MS (m/e): 494 (MH⁺).7.3.541N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-methyl-N-(2-hydroxyethyl)amino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926766) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand N-methyl-N-2-hydroxyethylamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-methyl-N-(2-hydroxyethyl)amino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.93 (d, 1H, J=3 Hz), 7.92 (bs, 1H), 7.35 (t, 1H, J=2.4Hz), 7.18 (m, 1H), 7.06 (dd, 1H, J=1.2 and 8.7 Hz), 6.97 (t, 1H, J=2.4Hz), 6.94 (m, 1H), 6.85 (d, 1H, J=8.7 Hz), 6.70 (bd, 1H), 6.59 (dd, 1H,J=1.8 and 8.1 Hz), 4.66 (s, 2H), 4.28 (s, 4H), 3.79 (t, 2H, J=5.4 Hz),3.56 (t, 3H, J=5.4 Hz), 3.10 (s, 3H); LCMS: ret. time: 16.64 min.;purity: 97%; MS (m/e): 470 (MH⁺). 7.3.542N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926767) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand homopiperazine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-homopiperazinocarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.27 (s, 1H), 9.17 (d, 1H, J=1.2 Hz), 8.14 (s, 1H),8.05 (d, 1H, J=3.6 Hz), 7.54-7.46 (m, 2H), 7.30 (d, 1H, J=2.4 Hz), 7.24(s, 1H), 7.17 (dd, 1H, J=2.4 and 8.7 Hz), 6.80 (d, 1H, J=8.7 Hz), 4.22(s, 4H), 3.79 (m, 2H), 3.65 (m, 2H), 3.01 (m, 2H), 2.89 (m, 2H), 1.90(m, 1H), 1.80 (m, 1H); ¹⁹F NMR (DMSO-d₆): - 46687; LCMS: ret. time:14.99 min.; purity: 77%; MS (m/e): 505 (MH⁺). 7.3.543N4-(3,4-Ethylenedioxyphenyl)-N2-[3-(N,N-dimethylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R925755) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand N,N-dimethylamine hydrochloride gaveN4-(3,4-ethylenedioxyphenyl)-N2-[3-(N,N-dimethylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.16 (d, 1H, J=1.2 Hz), 9.15 (s, 1H), 8.04 (d, 1H),J=5.6 Hz), 7.30-7.21 (m, 4H), 7.06 (t, 1H, J=9Hz), 6.78 (d, 1H, J=9Hz),6.43 (m, 1H), 4.65 (s, 2H), 4.21 (s, 4H), 2.94 (s, 3H), 2.82 (s, 3H);LCMS: ret. time: 18.70 min.; purity: 83%; MS (m/e): 440 (MH⁺). 7.3.544N2-[3-[N,N-Bis-(2-hydroxyethylamino)]carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926781) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand N,N-bis(hydroxyethyl)amine gaveN2-[3-[N,N-bis-(2-hydroxyethylamino)]carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.86 (d, 1H, J=3.6 Hz), 7.25 (m, 2H), 7.17-7.03 (m,3H), 6.78 (d, 1H, J=9Hz), 6.58 (bd, 1H), 4.80 (s, 2H), 4.23 (s, 4H),3.71 (t, 4H, J=4.8 Hz), 3.53 (t, 2H, J=6Hz), 3.49 (t, 3H, J=5.4 Hz);LCMS: ret. time: 16.25 min.; purity: 94%; MS (m/e): 500 (MH⁺). 7.3.545N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926782) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand 2,3-dihydroxypropylamine gaveN2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.86 (d, 1H, J=4.2 Hz), 7.37 (t, 1H, J=1.8 Hz), 7.24(d, 1H, J=2.4 Hz), 7.14 (m, 2H), 7.09 (dd, 1H, J=2.4 and 9 Hz), 6.78 (d,1H, J=8.7 Hz), 6.59 (m, 1H), 4.39 (s, 2H), 4.22 (s, 4H), 3.73 (m, 1H),3.48 (m, 4H); ¹⁹F NMR (CD₃OD): - 47575; LCMS: ret. time: 15.97; purity:98%; MS (m/e): 486 (MH⁺). 7.3.546N2-[2-(N-2,3-Dihydroxypropylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926783) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand 2,3-dihydroxypropylamine gaveN2-[2-(N-2,3-dihydroxypropylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.86 (d, 1H, J=4.2 Hz), 7.35 (t, 1H, J=1.2 Hz), 7.24(d, 1H, J=3 Hz), 7.15 (m, 2H), 7.07 (dd, 1H, J=2.1 and 8.7 Hz), 6.78 (d,1H, J=8.7 Hz), 6.59 (m, 1H), 4.40 9s, 1H), 4.23 (s, 4H), 4.03 (t, 1H,J=5.7 Hz), 3.67 (d, 2H, 3.6 Hz), 3.65 (d, 2H, J=4.2 Hz); ¹⁹F NMR(CD₃OD): -47578; LCMS: ret. time: 15.72 min.; purity: 99%; MS (m/e): 486(MH⁺). 7.3.547 N2-[3-(N-1,3-Dihydroxy-2-propylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926784) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethylenedioxyphenyl)-2,4-pyrimidinediamineand 2-amino-1,3-propanediol gaveN2-[3-(N-1,3-dihydroxy-2-propylamino)carbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.08 (bd, 1H), 7.86 (bs, 1H), 7.44 (s, 2H), 7.39 (s,1H), 7.29 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=2.4 and 8.7 Hz), 6.78 (d,1H, J==8.7 Hz), 4.24 (s, 4H), 3.84 (m, 1H), 3.56 (m, 2H), 3.44 (m, 2H);LCMS: ret. time: 16.63 min.; purity: 97%; MS (m/e): 496 (MH⁺). 7.3.548N2-[2-(N-1,3-Dihydroxy-2-propylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926785) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand 2-amino-1,3-propanediol gaveN2-[2-(N-1,3-dihydroxy-2-propylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.08 (t, 1H, J=1.8 Hz), 7.86 (d, 1H, J=3.9 Hz), 7.45(s, 2H), 7.41 (s, 1H), 7.29 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=3 and 8.7Hz), 6.77 (d, 1H, J=8.7 Hz), 4.24 (s, 4H), 4.19 (t, 1H, J=5.7 Hz), 3.75(d, 4H, J=5.4 Hz); ¹⁹F NMR (CD₃OD): - 47745; LCMS: ret. time: 15.09min., purity: 97%; MS (m/e): 496 (MH⁺). 7.3.549N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R940265) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-chloro-4-hydroxy-5-methylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith morpholine gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.66 min.; purity: 92 %; MS (m/e): 487 (M⁺), 489(MH⁺); ¹H NMR (DMSO-d₆): 9.28 (2H, s), 9.01 (1H, s), 8.17 (1H, d, J=3.6Hz), 7.65 (1H, d, J=2.4 Hz), 7.5 (1H, d, J=2.7 Hz), 7.42 (1H, d, J=6.6Hz), 7.29 (1H, s), 7.18 (1H, t, J=8.1 Hz), 6.57 (1H, dd, J=6.6 and 2.2Hz), 4.79 (2H, s), 3.67 (4H, m), 3.52 (4H, m), 2.29 (3H, s). 7.3.550N4-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950187)N4-(3,5-Dichlorophenyl-4-hydroxy)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(0.5 g, 1.1 mmol) was dissolved in EtOH:morpholine (4 ml : 4ml) and themixture was refluxed for 1 day (100° C. oil-bath temperature). Themixture was cooled to 22° C., diluted with water and brine, filtered,and dried under reduced pressure to giveN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.35 (s, 1H), 9.22 (s, 1H), 8.09 (d, 1H, J=3.6 Hz),7.94 (m, 1H), 7.75 (m, 1H), 7.27 (m, 1H), 7.18 (m, 1H), 7.12 (t, 1H,J=8.4 Hz), 6.44 (m, 1H), 4.64 (s, 2H), 3.39 (m, 4H), 2.68 (m, 4H); LCMSpurity: 92.6%; MS (m/e): 507.89 (M⁺, 100). 7.3.551N4-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950188) In like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,5-dichloro-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamineand piperazine were reacted to prepareN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 15.26 min.; purity: 88.5%; MS (m/e): 506.89 (MH⁺).7.3.552N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyeleneoxyphenyl]-2,4-pyrimidinediamine(R926776) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3-ethoxycarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyeleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 16.94 min.; purity: 73%; MS (m/e): 426 (MH⁺). 7.3.553N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945173) In a manner analogous to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-(4-methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine,N4-(4-cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ2.80 (d, 3H), 4.21-4.28 (m, 4H), 4.47 (s, 2H),6.71 (d, J=8.7 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 7.06 (dd, J=2.7 and 9.0Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.93 (d, J=3.6Hz, 1H), 8.20 (br, 1H, NH), 8.41 (br, 1H, NH); ¹⁹F NMR (282 MHz,acetone-d₆): δ- 169.05; LCMS: ret. time: 17.47 min.; purity: 98.99%; MS(m/e): 425.89 (MH⁺). 7.3.554N2-[4-(2-N,N-Dimethylaminoethyl)oxyphenyl]-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909253) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-4-pyrimidineamine and 4-(2-N,N-dimethylaminoethyl)oxyanilinewere reacted to yieldN2-[4-(2-N,N-dimethylaminoethyl)oxyphenyl]-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.0 (d, 1H J=4 Hz), 7.42 (m, 2H), 7.24 (m, 2H), 7.05(m, 2H), 6.85 (m, 1H), 4.39 (s, 2H), 4.30 (m, 2H), 3.66 (m, 2H), 3.04(s, 6H), 2.83 (s, 3H); LCMS: ret. time: 14.0 min.; purity: 96 %; MS(m/e): 455 (MH⁺). 7.3.555N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909247) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-4-pyrimidineamine and 6-amino-1,4-benzoxazine were reacted toyieldN2-(1,4-benzoxazin-6-yl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H (DMSO-d₆): δ8.0 (d, 1H), 7.6 (m, 1H), 7.42 (m, 1H), 7.20 (m, 1H),6.95 (m, 1H), 6.76 (m, 1H), 6.56 (m, 1H), 4.43 (s, 2H), 4.05 (m, 2H),3.25 (s, 3H), 3.13 (m, 2H); LCMS: ret time: 17.67 min.; MS (m/e): 425(MH⁺). 7.3.556N2-(4-Dihydrobenzofuranyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909249) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-4-pyrimidineamine and 5-amino-2,3-dihydrobenzofuran werereacted to yieldN2-(4-dihydrobenzofuranyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ8.09 (d, 1H), 8.00(m, 1H), 7.42 (m, 2H), 7.05 (m, 1H), 6.96 (m, 1H), 6.76 (m, 1H), 6.58(m, 1H), 4.53 (m, 2H), 4.25 (s, 2H), 3.15 (m, 2H), 2.70 (m, 3H); LCMS:ret time: 19.24 min; MS (m/e): 410 (MH⁺). 7.3.557N2-(3-tert-Butylphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R940267) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3-tert-butylphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN2-(3-tert-butylphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 22.22 min.; purity: 97 %; MS (m/e): 424 (MH⁺); ¹H NMR(CDCl₃): δ7.98 (2H, m), 7.76 (2H, m), 7.56 (1H, t, J=1.3 Hz), 7.28-7.22(1H, m), 7.04 (1H, d, J=7.8 Hz), 6.90 (1H, dd, J=9 Hz, J=1.3 Hz), 6.80(1H, 2.6 Hz), 6.66 (1H, dd, J=9 and 2.6 Hz), 6.46 (1H, s), 4.53 (2H, s),2.88 (3H, d, J=5.1 Hz), 1.31 (9H, s). 7.3.558N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R926491) In like manner to the preparation ofN4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-(3,4-ethylenedioxyphenyl)-N4-(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.10 (s, 1H), 7.94 (d, 1H, J=5.1 Hz), 7.59 (s, 2H),7.44 (s, 1H), 6.96 (d, 1H, J=2.4 Hz), 6.82 (d, 1H, J=8.4 Hz), 6.76 (dd,1H, J=3.6 and 8.1 Hz), 4.22 (s, 2H), 4.21 (s, 2H), 2.95 (s, 3H); LCMS:ret. time: 17.76 min.; purity: 97%; MS (m/e): 436 (MH⁺). 7.3.559N2-(3,5-Dimethoxyphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926810) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine,the reaction ofN2-(3,5-dimethoxyphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith methylamine hydrochloride gaveN2-(3,5-dimethoxyphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.93 (d, 1H, J=3.9 Hz), 7.72 (t, 1H, J=1.8 Hz),7.27-7.19 9m, 2H), 6.88 (d, 2H, J=2.4 Hz), 6.72 (m, 1H), 6.01 (t, 1H,J=2.4 Hz), 4.44 (s, 2H), 3.67 (s, 6H), 2.80 (s, 3H). 7.3.5605-Bromo-N2-(3,4-ethylenedioxyphenyl)-N4-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925851) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-bromo-N2-(3,4-ethylenedioxyphenyl)-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yield5-bromo-N2-(3,4-ethylenedioxyphenyl)-N4-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.01 (s, 1H), 7.48 (d, 2H, J=8.7 Hz), 7.09 (d, 1H,J=3.0 Hz), 7.08 (d, 2H, J=8.7 Hz), 6.81 (dd, 1H, J=8.7 Hz), 6.64 (d, 1H,J=8.7 Hz), 4.52 (s, 2H), 4.20 (bs, 4H), 2.83 (s, 3H); LCMS: ret. time:19.13 min.; purity: 94 %; MS (m/e): 487 (MH⁺). 7.3.561N2-(3-Hydroxyphenyl)-5-trifluoromethyl-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926741) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-(3-hydroxyphenyl)-5-trifluoromethyl-N4-(3-N-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN2-(3-hydroxyphenyl)-5-trifluoromethyl-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.52 min.; purity: 96%; MS (m/e): 434 (MH⁺). 7.3.562N2,N4-Bis[4-(N-n-butylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925860) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand n-butylamine were reacted to yieldN2,N4-bis[4-(N-n-butylamino)carbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ9.77 (bs,1H), 9.38 (bs, 1H), 8.42 (s, 1H), 8.09 (t, 1H, J=5.4 Hz), 8.02 (t, 1H,J=5.7 Hz), 7.48-7.34 (m, 4H), 6.93 (d, 2H, J=9.3 Hz), 6.82-6.72 (m, 2H),4.47 (s, 2H), 4.38 (s, 2H), 3.14-3.06 (m, 4H), 1.42-1.33 (m, 4H),1.28-1.18 (m, 4H), 0.83 (t, 6H, J=6.9 Hz); LCMS: ret. time: 26.40 min.;purity: 97 %; MS (m/e): 546 (MH⁺). 7.3.563N2,N4-Bis[4-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925861) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand isopropylamine were reacted to yieldN2,N4-bis[4-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ8.41 (s,1H), 7.90 (d, 1H, J=7.5 Hz), 7.81 (d, 1H, J=7.5 Hz), 7.50-7.36 (m, 4H),6.93 (d, 2H, J=8.7 Hz), 6.84-6.75 (m, 2H), 4.45 (s, 2H), 4.36 (s, 2H),3.99-3.87 (m, 2H), 1.08 (d, 6H, J=3.0 Hz), 1.06 (d, 6H, J=2.4 Hz); LCMS:ret. time: 23.45 min.; purity: 89 %; MS (m/e): 518 (MH⁺). 7.3.564N2,N4-Bis[4-(N-n-propylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine (R925853) In a manner similarto the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand n-propyl amine were reacted to yieldN2,N4-bis[4-(N-n-propylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.78 (bs, 1H), 9.38 (bs, 1H), 8.41 (s, 1H), 8.07 (dt,2H, J=6.0 and 22.5 Hz), 7.48-7.36 (m, 4H), 6.93 (d, 2H, J=8.7 Hz), 6.78(d, 2H, J=8.1 Hz), 4.48 (s, 2H), 4.39 (s, 2H), 3.07 (2q, 4H, J=7.2 Hz),1.47-1.38 (m, 4H), 0.90-0.77 (m, 6H); LCMS: ret. time: 23.67 min.;purity: 94 %; MS (m/e): 519 (MH⁺). 7.3.565N2,N4-Bis[4-(N-morphonlino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925854) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand morpholine were reacted to yieldN2,N4-bis[4-(N-morphonlino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.78 (bs, 1H), 9.31 (bs, 1H), 8.41 (s, 1H), 7.43 (d,4H, J=8.1 Hz), 6.89 (d, 2H, J=9.3 Hz), 6.75 (d, 2H, J=8.4 Hz), 4.84 (s,2H), 4.74 (s, 2H), 3.76 (t, 4H, J=5.1 Hz), 3.62-3.50 (m, 4H), 3.49-3.38(m, 4H), 3.08-3.01 (m, 4H); LCMS: ret. time: 19.25 min.; purity: 89 %;MS (m/e): 574 MH⁺). 7.3.566N2,N4-Bis[4-(N-piperidino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925855) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand piperidine were cted to yieldN2,N4-bis[4-(N-piperidino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (acetone-d₆): δ8.86 (bs, 1H), 8.48 (bs, 1H), 8.34 (s, 1H),7.61-7.50 (m, 4H), 6.98 (d, 2H, J=8.7 Hz), 6.90 (d, 2H, J=9.3 Hz), 4.84(s, 2H), 4.75 (s, 2H), 3.59-3.48 (m, 8H), 1.68-1.44 (m, 12H); LCMS: ret.time: 24.76 min.; purity: 98 %; MS (m/e): 571 (MH⁺). 7.3.567N2,N4-Bis[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine(R925859) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand cyclopropylmethylamine were reacted to yieldN2,N4-bis[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.78 (bs, 1H), 9.36 (bs, 1H), 8.41 (s, 1H), 8.18 (t,1H, J=5.1 Hz), 8.10 (t, 1H, J=5.1 Hz), 7.52-7.38 (m, 4H), 6.94 (d, 2H,J=8.7 Hz), 6.84-6.76 (m, 2H), 4.48 (s, 2H), 4.40 (s, 2H), 3.00 (q, 4H,J=6.3 Hz), 0.97-0.88 (m, 2H), 0.40-0.33 (m, 4H), 0.18-0.03 (m, 4H); ¹⁹FNMR (CDCl₃): LCMS: ret. time: 24.58 min.; purity: 100 %; MS (m/e): 543(MH⁺). 7.3.568N4-(3-Aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950254)N4-(3-Nitrophenyl)-N2-[(2H)1,4-benzoxazin-3(4H)-one-6-yl]-5-fluoro-2,4-pyrimidinediamine(940 mg, 2.5 mmol) and Pd/C 10% (300 mg, 50% water content) weresuspended in EtOH (7 mL) and 10% aqueous HCl (5 mL) and hydrogenated ina Parr apparatus for 3 hours (22° C., 60 psi). The suspension wasfiltered over celite and neutralized by addition of K₂CO₃. The solventswere removed and the resulting black slurry was suspended in MeOH.Silica gel (4 g) was added and the volatiles were removed under reducedpressure. The residue was subjected to column chromatography on silicagel (CHCl₃-Acetone, 2:1) to give 186 mg ofN4-(3-aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineas brownish solid. ¹H NMR (DMSO-d₆): δ8.92 (s, 1H), 8.64 (s, 1H), 7.95(d, 1H, J=3.6 Hz), 7.11 (s, 1H), 6.84-6.95 (m, 3H), 6.66 (dd, 1H, J=2.4,9.0 Hz), 6.46 (d, 1H, J=8.1 Hz), 6.28 (d, 1H, J=8.1 Hz), 5.62 (s, 1H),4.98 (s, 2H), 4.03 (m, 2H), 3.31 (m, 2H); LCMS purity: 98.4%; MS (m/e):352.7 (M⁺, 100). 7.3.569N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950200)N2-(3-Ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(50 mg, 0.11 mmol) was dissolved in EtOH:4-(2-aminoethyl)morpholine (0.5ml : 0.5 ml) and the mixture was refluxed for 3 hours (100° C. oil-bathtemperature). The mixture was cooled to 22° C., diluted with water andwashed with EtOAc. The organic phase was dried over MgSO₄, concentratedunder educed pressure, and the residue was subjected to columnchromatography on silica gel (CHCl₃:Acetone, 2:1) to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆ +CD₃OD): δ7.92 (d, 1H, J=4.1 Hz), 7.31 (d, 1H, J=2.3 Hz), 7.20 (dd, 1H,J=2.7, 8.8 Hz), 6.87-6.99 (m, 2H), 6.74 (d, 1H, J=8.8Hz), 6.09 (m, 1H),4.19 (m, 4H), 3.38 (m, 4H), 3.16 (t, 2H, J=6.3 Hz), 2.28 (t, 2H, J=6.3Hz); LCMS purity: 99.2%; MS (m/e): 524.01 (M⁺, 100). 7.3.570N4-(3,4-Ethylenedioxyphenyl)-N2-[3-N-methylamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950191) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand methylamine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 17.32 min.; purity: 99.3%; MS (m/e): 425.04 (MH⁺).7.3.571N2-[3-(N-Amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950192) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand aqueous ammonia were reacted to prepareN2-[3-(N-amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 16.59 min.; purity: 98.8%; MS (m/e): 411.02 (MH⁺).7.3.572N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950193) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand morpholine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 18.70 min.; purity: 85.8%; MS (m/e): 481.05 (MH⁺).7.3.573N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-(N-methyl)-piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950194) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand N-methylpiperazine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-(N-methyl)piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 15.75min.; purity: 99.1%; MS (m/e): 494.06 (MH⁺). 7.3.574N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxyethyleneamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950195) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand 2-aminoethanol were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxyethyleneamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 16.23 min.; purity: 97.3%; MS (m/e): 455.02 (MH⁺).7.3.575N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)ethyleneaminocarbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950196) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand N-methyl-ethylen-1,2-diamine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)ethyleneaminocarbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 15.34min.; purity: 98.2%; MS (m/e): 468.06 (MH⁺). 7.3.576N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950197) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand piperazine were reacted to prepareN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.38 min.; purity: 93.2%; MS (m/e): 479.99 (MH⁺).7.3.577N2-[3-(N-Benzylamino)ethyleneaminocarbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950198) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand N-benzyl-ethylen-1,2-diamine were reacted to prepareN2-[3-(N-benzylamino)ethyleneaminocarbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 17.70 min.; purity: 92.5%; MS (m/e): 544.04 (MH⁺).7.3.578N2-[3-(N,N′-Bis(2-N-hydroxyethyl)amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-imidinediamine(R950199) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand N,N′-bis(2-hydroxyethylene)amine were reacted toN2-[3-(N,N′-bis(2-N-hydroxyethyl)amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 15.81 min.; purity: 99.4%; MS (m/e): 499.01 (MH⁺).7.3.5795-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950217) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand methylamine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 14.41 min.; purity: 93.0%; MS (m/e): 383.02 (MH⁺).7.3.580N2-(3-Aminocarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950219) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand aqueous ammonia were reacted to prepareN2-(3-aminocarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 14.23 min.; purity: 95.0%; MS (m/e): 369.03 (MH⁺).7.3.581N2-[3-(N,N-Dimethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R950220) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand dimethylamine were reacted to prepareN2-[3-(N,N-dimethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 16.59 min.; purity: 96.5%; MS (m/e): 397.06 (MH⁺).7.3.5825-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950221) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand morpholine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 16.29 min.; purity: 91.5%; MS (m/e): 439.03 (MH⁺).7.3.5835-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950222) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand piperazine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 13.04 min.; purity: 89.9%; MS (m/e): 438.06 (MH⁺).7.3.5845-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[N-(N-methyl)piperazino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950223) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand N-methylpiperazine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[N-(N-methyl)piperazino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.06 min.; purity: 98.7%; MS (m/e): 452.06 (MH⁺).7.3.5855-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950224) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand 2-aminoethanol were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 13.28 min.; purity: 97.3%; MS (m/e): 413.04 (MH⁺).7.3.5865-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950225) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand N-methyl-ethylen-1,2-diamine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.31 min.; purity: 94.7%; MS (m/e): 426.01 (MH⁺).7.3.5875-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-2-morpholinoethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950226) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand N-morpholinylethylamine were reacted to prepare5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-morpholinoethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.66 min.; MS (m/e): 482.39 (MH⁺). 7.3.588 R935184:5-Fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediaminewas reacted with Me₂NH.HCl and i-Pr₂NEt in methanol to produce5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 6.91 min.; purity: 98%; MS (m/e): 440 (MH⁺). 7.3.589R935196:N2-[3-(1-Bis(N-methylaminocarbonyl)ethoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidineamine:In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[3-(1-bis(ethyloxycarbonyl)ethoxy)phenyl]-5-fluoro-N2-[4-isopropoxyphenyl)-2,4-pyrimidinediaminewas reacted with Me₂NH.HCl and i-Pr₂NEt in presence of methanol toproduceN2-[3-(1-bis(N-methylaminocarbonyl)ethoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidineamine.¹H NMR (DMSO-d₆): δ9.18 (s, 1H), 9.15 (s, 1H), 8.07 (app qt, 2H, J=4.7Hz), 8.01 (d, 1H, J=3.5 Hz), 7.65-7.62 (m 2H), 7.36 (br s, 1H), 7.28(dd, 1H, J=1.1 and 8.2 Hz), 7.03 (t, 1H, J=8.2 Hz), 6.87 (d, 2H, J=8.8Hz), 6.35 (dd, 1H, J=1.1 and 8.8 Hz), 4.54 (q, 1H, J=6.4 Hz), 2.62 (d,6H, J=4.7 Hz), 1.49 (s, 3H), 1.23 (d, 6H, J=5.8 Hz). LCMS: ret. time:19.40 min.; purity: 94%; MS (m/e): 497 (MH⁺). 7.3.590 R935202:5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine:In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediaminewas reacted with Me₂NH.HCl to give5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.21 (s, 1H), 9.19 (s, 1H), 8.06 (d, 1H, J=4.1 Hz),7.94 (q, 1H, J=3.5 Hz), 7.42-7.38 (m, 2H), 7.30 (d, 2H, J=7.6 Hz), 7.12(t, 1H, J=7.6 Hz), 6.89 (d, 1H, J=8.2 Hz), 6.47 (dd, 1H, J=2.3 and 8.8Hz), 4.33 (s, 2H), 4.11-4.03 (m, 4H), 2.63 (d, 3H, J=4.7 Hz)), 2.08-2.03(m, 2H). LCMS: ret. time: 17.33 min.; purity: 98%; MS (m/e): 440 (MH⁺).7.3.591 R935206: N2,N4-Bis[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamineand was reacted with Me₂NH.HCl and i-PrN₂Et in presence of methanol toproduce N2,N4-bis[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.56 (s, 1H), 9.40 (s, 1H), 8.17 (d, 1H, J=3.5 Hz),8.12 (s, 1H), 7.99 (s, 1H), 7.96 (s, 2H), 7.90 (s, 2H), 7.66 (d, 1H,J=8.8 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.49 (dd, 1H, J=1.7 and 8.8 Hz), 7.34(dd, 1H, J=1.7 and 8.8 Hz), 4.90 (s, 2H), 4.66 (s, 2H), 2.56 (d, 6H,J=4.11 Hz). LCMS: ret. time: 13.85 min.; purity: 98%; MS (m/e): 503(MH⁺). 7.3.592 R935212:N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineand Me₂NH.HCl was reacted to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.35 (s, 1H), 9.17 (s, 1H), 8.07 (d, 1H, J=4.8 Hz),7.92 (s, 1H), 7.89 (s, 1H), 7.66 (q, 1H, J=4.7 Hz), 7.54 (d, 1H, J=8.8Hz), 7.35-7.24 (m, 3H), 6.76 (d, 1H, J=8.8 Hz), 4.77 (s, 2H), 4.20 (s,4H), 2.57 (d, 3H, J=4.7 Hz). LCMS: ret. time: 15.82 min.; purity: 94%;MS (m/e): 450 (MH⁺). 7.3.593 R935213:N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-(N-methylamino)carbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediaminewas reacted with Me₂NH.HCl and i-Pr₂NEt. to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-(N-methylamino)carbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.17 (s, 2H), 8.30 (q, 1H, J=4.7 Hz), 8.05 (d, 1H,J=3.5 Hz), 7.42 (s, 1H), 7.29-7.19 (m, 2H), 7.09 (t, 1H, J=8.2 Hz), 7.02(d, 1H, J=2.9 Hz), 6.76 (d, 1H, J=8.8 Hz), 6.67 (d, 1H, J=2.9 Hz), 6.54(dd, 1H, J=1.7 and 8.2 Hz), 4.94 (s, 2H), 4.21-4.18 (m, 4H), 2.70 (d,3H, J=4.7 Hz). LCMS: ret. time: 18.85 min.; purity: 91%; MS (m/e): 492(MH⁺). 7.3.594 R935216:5-Fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 9.00 (s, 1H), 8.17 (s, 1H), 8.02 (d,1H, J=3.5 Hz), 7.99 (m, 1H), 7.93 (s, 1H), 7.59 (m, 2H), 7.52 (d, 2H,J=8.8 Hz), 6.78 (d, 2H, J=8.8 Hz), 4.36 (s, 2H), 4.03 (s, 3H), 2.63 (d,3H, J=4.7 Hz). LCMS: ret. time: 14.81 min.; purity: 99%; MS (m/e): 422(MH⁺). 7.3.595 R935217: N2,N4-Bis[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2,N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to produce N2,N4-bis[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.35 (s, 1H), 9.15 (s, 1H), 8.09-8.06 (m, 2H),7.97-7.96 (m, 2H), 7.91 (s, 1H), 7.70 (s, 1H), 7.69 (s, 1H), 7.64-7.55(m, 2H), 7.48-7.40 (m, 2H), 5.06 (s, 2H), 4.97 (s, 2H), 2.62 (d, 3H,J=4.7 Hz), 2.61 (d, 3H, J=4.7 Hz). LCMS: ret. time: 12.54 min.; purity:95%; MS (m/e): 503 (MH⁺). 7.3.596N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926486) A dry reaction vial equipped with a rubber septum was chargedwithN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(0.019 g, 0.04 mmol) and THF (1 mL). To this was added boranemethylsulfide complex (0.044 mL, 0.088 mmol) and stirred at room temperaturefor 2 h. The amount of boranemethyl sulfide complex was evaporated andthe reaction was quenched with MeOH (CAUTION: vigorous evolution ofhydrogen gas occurs during the addition of MeOH), heated for 30 min. Thesolvent was removed and again the residue was suspended in MeOH,extracted with EtOAc, EtOAc was evaporated and the residue was purifiedby preparative TLC to obtainN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.20 (s, 1H), 8.01 (d, 1H, J=6 Hz), 7.26-7.05 (m, 3H),7.05-6.97 (m, 3H), 6.82 (d, 1H, J=9.3 Hz), 6.67 (dd, 1H, J=1.8 and 8.1Hz), 4.44 (t, 2H), 4.27 (s, 4H), 4.14 (m, 2H), 3.76 (m, 2H), 3.22 (t,2H, J=5.4 Hz), 3.05 (m, 2H), 2.88 (m, 2H). 7.3.597N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine(R926490) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediaminewith boranemethyl sulfide complex gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.65 (d, 2H, J=2.1 Hz), 8.30 (dd, 2H, J=2.1 and 9.6Hz), 7.73 (d, 2H, J=9.3 Hz), 7.49 (bs, 2H), 7.32 (m, 1H), 6.74 (m, 1H),4.24 (s, 4H), 3.97 (s, 2H), 3.78 (m, 4H), 3.56 (m, 4H). 7.3.598N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926510) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand boranemethyl sulfide complex gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.00 (d, 1H, J=5.2 Hz), 7.50-7.30 (m, 2H), 7.16- 6.80(m, 5H), 4,28 (m, 1H), 4.27 (bs, 4H), 4.22 (m, 1H), 3.44 (m, 2H), 2.79(d, 3H, J=3Hz); LCMS: ret. time: 15.64 min.; purity: 96%; MS (m/e): 412(MH⁺). 7.3.5995-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine(R926770) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediaminewith boranemethyl sulfide complex gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.06 min.; purity: 75%; MS (m/e): 435 (MH⁺). 7.3.600N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine(R940255) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith boranemethyl sulfide complex gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 15.94 min.; purity: 99 %; MS (m/e): 454 (MH⁺); ¹H NMR(DMSO-d₆): δ9.16 (1H, s), 9.07 (1H, s), 8.15 (1H, s), 8.11 (1H, d, J=3.9Hz), 7.40-7.30 (4H, m), 7.13 (1H, t, 8.1 Hz), 6.55 (1H, dd, J=8.1 Hz,3.2 Hz), 4.01 (2H, t, J=5.7 Hz), 3.65 (4H, t, J=4.2 Hz), 2.72 (2H, t,J=5.7 Hz), 2.515 (4H, t, J=4.5 Hz), 2.24 (6H, s). 7.3.601N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediaminebis Hydrogen Chloride Salt (R945142) In like manner to the preparationofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewas treated with boranemethyl sulfide complex to giveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethyloxy]phenyl]-2,4-pyrimidinediamine,which was then treated with 4N HCl in dioxane (3 mL) followedcrystallization from MeOH/EtOAc to giveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediaminebis Hydrogen Chloride Salt. ¹H NMR (CD₃OD): δ2.17 (s, 6H), 3.66 (m,10H), 4.26 (t, J=4.5 Hz, 2H), 6.93 (dd, J=1.5, 7.2 Hz, 1H), 7.10-7.13(m, 2H), 7.17 (s, 2H), 7.31 (t, J=8.4 Hz, 1H), 7.98 (d, J=6.0 Hz, 1H);¹⁹F NMR (282 MHz, CD₃OD): δ- 162.93; LCMS: ret. time: 13.25 min.;purity: 96.08%; MS (m/e): 453.09 (MH⁺). 7.3.602N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(2-hydroxyethyloxy)phenyl]-2,4-pyrimidinediamine(R945144) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,the reaction ofN2-(4-carboxymethyleneoxyphenyl)-N4-(3,4-ethylendioxyphenyl)-5-fluoro-2,4-pyrimidinediamineand boranemethyl sulfide complex gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (acetone-d ₆): δ3.86 (t, J=4.8 Hz, 2H), 4.04 (t, J=4.8 Hz, 2H),4.28 (m, 4H), 6.78 (d, J=9.0 Hz, 1H), 6.86 (d, J=9.0 Hz, 2H), 7.18 (dd,J=2.7, 8.7 Hz, 1H), 7.47 (d, J=2.7 Hz, 1H), 7.63 (d, J=9.0 Hz, 2H), 7.91(d, J=3.6 Hz, 1H), 8.29 (br, 1H, NH), 8.31 (br, 1H, NH); ¹⁹F NMR (282MHz, acetone-d ₆): δ- 169.18; LCMS: ret. time: 17.41 min.; purity:98.36%; MS (m/e): 399.01 (MH⁺). 7.3.603N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediamineDihydrochloride Salt (R945150) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewas treated with boranemethyl sulfide complex to giveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethyloxy]phenyl]-2,4-pyrimidinediamine,which was then treated with 4N HCl in dioxane (3 mL) followedcrystallization from MeOH/EtOAc to giveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediaminebis Hydrogen Chloride Salt. ¹H NMR (CD₃OD): δ2.21 (s, 3H), 3.72 (m,10H), 4.35 (t, J=4.5 Hz, 2H), 6.95 (dt, J=1.5 and 9.0 Hz, 1H), 7.11-7.14(m, 2H), 7.26 (dd, J=0.9 and 2.7 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.50(d, J=2.4 Hz, 1H), 8.03 (d, J=5.4 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ-162.74; LCMS: ret. time: 14.50 min.; purity: 94.75%; MS (m/e): 472.98(MH⁺). 7.3.604N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediamineDihydrochloride Salt (R945157) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewas treated with boranemethyl sulfide complex to giveN4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethyloxy]phenyl]-2,4-pyrimidinediamine,which was then treated with 4N HCl in dioxane (3 mL) followedcrystallization from MeOH/EtOAc to giveN4-5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediaminebis Hydrogen Chloride Salt. ¹H NMR (CD₃OD): δ2.23 (s, 6H), 3.66 (m,10H), 3.72 (s, 3H), 4.31 (t, J=4.5 Hz, 2H), 6.95 (dd, J=1.8 and 8.4 Hz,1H), 7.09-7.15 (m, 2H), 7.27 (s, 2H), 7.32 (t, J=8.1 Hz, 1H), 8.01 (d,J=5.4 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ- 162.71; LCMS: ret. time:16.41 min.; purity: 97.50%; MS (m/e): 467.12 (MH⁺). 7.3.605N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926501) The reaction of equivalent amount ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) in methanol at 0° C. followed bydilution with dry ethyl ether or ethyl acetate gave the precipitate. Theresulting precipitate was isolated by filtration (and/or usingcentrifuse technique) to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (CD₃OD): δ7.97 (d, 1H, J=5.4 Hz), 7.92(d, 1H, J=1.8 Hz), 7.62 (d, 1H, J=8.2 Hz), 7.48 (s, 1H), 7.43 (dd, 1H,J=J=2.4 and 8.7 Hz), 7.17 (d, 1H, J=2.4 Hz), 6.98 (dd, 1H, J=2.4 and 8.7Hz), 6.77 (d, 1H, J=8.7 Hz), 4.13 (m, 4H), 4.22 (s, 4H), 3.38 (t, 4H,J=5.7 Hz); LCMS: ret. time: 15.12 min; purity: 89%; MS (m/e): 491 (MH⁺).7.3.606N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926504) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydrogen chloride gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt. ¹H NMR(DMSO-d₆): δ9.6 (bs, 1H), 9.04 (bs, 1H), 8.12 (d, 1H, J=3.6 Hz),7.25-7.00 (m, 5H), 7.81 (d, 1H, J=8.7 Hz), 6.54 (d, 1H, J=8.4 Hz), 4.74(s, 2H), 4.22 (s, 4H), 3.64 (m, 4H), 3.11 (m, 4H); LCMS: ret. time:15.34 min.; purity: 100%; MS (m/e): 481 (MH⁺). 7.3.607N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-N-methylaminoethyl)phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926509) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyloxy]phenyl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. LCMS: ret. time: 15.88 min.; purity: 92%; MS(m/e): 412 (MH⁺). 7.3.608N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926511) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineand hydrogen chloride gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (CD₃OD): δ7.98 (d, 1H, J=5.4 Hz), 7.34(t, 1H, 8.4 Hz), 7.16-6.81 (m, 6H), 4.42 (m, 1H), 4.40 (m, 2H), 4.25 (m,5H), 4.10 (m, 2H), 3.90 (bs, 2H), 3.60 (m, 4H); LCMS: ret. time: 16.39min.; purity: 100%; MS (m/e): 468 (MH⁺). 7.3.609N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926768) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediaminewith hydrogen chloride treatment gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (DMSO-d₆): δ9.98 (bs, 1H), 9.05 (bs, 1H),8.18 (d, 1H, J=4.8 Hz), 8.01 (s, 1H), 7.58 (d, 1H, J=8.7 Hz), 7.50 (bd,1H), 7.35 (s, 1H), 7.24 (d, 1H, J=2.4 Hz), 7.11 (dd, 1H, J=3 and 9 Hz),6.80 (d, 1H, J=8.7 Hz), 4.22 (s, 4H), 4.20-3.60 (m, 8H), 3.20 (m, 2H);LCMS: ret. time: 14.91 min.; purity: 86%; MS (m/e): 505 (MH⁺). 7.3.6105-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt R926502) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt,5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineupon treatment with hydrogen chloride (4M, dioxane) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (CDC₃OD): δ8.00 (s, 1H), 7.89 (s, 1H),7.98 (s, 1H), 7.60 (d, 1H, J=8.7 Hz), 7.45 (m, 3H), 7.16 (t, 1H, J=8.1Hz), 7.10 (m, 1H), 7.02 (dd, 1H, J=1.2 and 7.2 Hz), 6.70 (dd, 1H, J=2.4and 8.4 Hz), 4.13 (m, 4H), 3.37 (t, 4H, J=5.4 Hz), 3.38 (t, 4H, J=5.7Hz); LCMS: ret. time: 13.40 min; purity: 79%; MS (m/e): 450 (MH⁺).7.3.6115-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamineDihydrochloride Salt (R926769) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamineDihydrochloride Salt. ¹H NMR (CD₃OD): δ8.00 (d, 1H), 7.85 (bd, 1H), 7.75(m, 3H), 7.60 (m, 2H), 7.40-7.15 (m, 4H), 7.05 (s, 1H), 7.00-6.800 (m,3H), 4.65 (dd, 2H), 3.60 (m, 8H). 7.3.6125-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926773) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt,5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydrogen chloride (4M, dioxane) gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (CD₃OD): δ7.99 (d, 1H, J=5.1 Hz), 7.29(t, 1H, J=8.1 Hz), 7.21-7.05 (m, 5H), 6.83 (dd, 1H, J=2.4 and 8.7 Hz),6.77 (bd, 1H), 4.79 (s, 2H), 3.83 (m, 2H), 3.78 (m, 2H), 3.25 (m, 2H);LCMS: ret. time: 12.27 min.; purity: 91%; MS (m/e): 439 (MH⁺). 7.3.613N2-[3-[2-(N,N-Dimethylamino)ethyloxy]phenyl]-N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineHydrogen Chloride Salt (R926771) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the treatment ofN4-(3,4-ethylenedioxyphenyl)-N2-[3-[2-(N,N-dimethylamino)ethyloxy]phenyl]-5-fluoro-2,4-pyrimidinediamine withequivalent amount of hydrogen chloride (4M, dioxane) gaveN4-(3,4-ethylenedioxyphenyl)-N2-[3-[2-(N,N-dimethylamino)ethyloxy]phenyl]-5-fluoro-2,4-pyrimidinediamine HydrogenChloride Salt. LCMS: ret. time: 15.37 min.; purity: 93%; MS (m/e): 426(MH⁺). 7.3.614N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R940256) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) gaveN4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. LCMS: ret. time: 15.78 min.; purity: 98 %; MS(M/e): 454 (MH⁺); 1H NMR (DMSO-d₆): δ10.60 (1H, s), 9.58 (1H, s), 8.29(1H, s), 8.20 (1H, s), 7.43 (1H, d, J=9Hz), 7.38-7.30 (3H, m), 7.24 (1H,t, J=9 Hz), 6.70 (1H, d, J=9 Hz), 4.35 (2H, m), 4.05 (2H, m), 3.84 (4H,m), 3.65-3.50 (2H, m), 3.26 (2H, m), 2.25 (6H, s). 7.3.615N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamine HydrogenChloride Salt (R940269) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the reaction ofN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) gaveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. LCMS: ret. time: 14.74 min.; purity: 96 %; MS(m/e): 474 (M⁺), 475 (MH⁺); ¹H NMR (DMSO-d₆): δ10.03 (1H, s), 9.35 (2H,s), 9.06 (1H, s), 8.17 (1H, d, J=3.9 Hz), 7.67 (1H, m), 7.52 (1H, m),7.46 (1H, d, J=8.7 Hz), 7.39 (1H, s), 7.24 (1H, t, J=8.1 Hz), 6.66 (1H,d, J=8.1 Hz), 4.33 (1H, m), 4.07 (1H, d, J=13 Hz), 3.79 (1H, t, J=12.5Hz), 3.56 (4H, m), 3.49 (4H, m), 3.29 (1H, t, J=12.5 Hz), 2.29 (3H, s).7.3.616N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R926816) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamineHydrogen Chloride Salt, the treatment ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewith equivalent amount of hydrohen chloride (4M, dioxane) gave theN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride salt. LCMS: ret. time: 17.04 min., purity: 96%, MS(m/e): 426 (MH+). 7.3.617N4-(3,4-Ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine(R926696) A dry reaction flask charged withN4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewas recated with diisobutylaluminum hydride (DIBALH) (5 equivalents) inCH₂Cl₂ at -78° C. (reaction was monitored by TLC) followed by treatmentwith Rochell′s salt to yieldN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.11 (s, 1H), 8.02 (d, 1H, J=3.3 Hz), 7.96 (t, 1H,J=1.8 Hz), 7.40-7.30 (m, 3H), 7.19 (dt, 1H, J=3.6 and 8.1 Hz), 6.78 (d,1H, J=8.7 Hz), 6.59 (s, 1H), 4.52 (d, 2H, J=5.1 Hz), 4.22 (s, 4H); ¹⁹FNMR (DMSO-d₆): - 46802; LCMS: ret. time: 19.14 min.; purity: 95 %; MS(m/e): 409 (MH⁺). 7.3.6185-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(hydroxymethyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine(R926700) In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-5-yl]-2,4-pyrimidinediaminewas reduced with DIBALH to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(hydroxymethyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.81 (d, 1H, J=4.2 Hz), 7.23 (d, 1H, J=1.8 Hz),7.28-7.23 (m, 2H), 7.19 (t, 1H, J=2.4 Hz), 7.12 (dd, 1H, J=1.8 and 9.0Hz), 7.07 (t, 1H, J=8.4 Hz), 6.52 (ddd, 1H, J=1.2 and 8.1 Hz), 6.30 (s,1H), 4.71 (s, 2H); ¹⁹F NMR (CD₃OD): - 47971; LCMS: ret. time: 15.36min.; purity: 100 %; MS (m/e): 366 (MH⁺). 7.3.6195-Fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-[4-(isopropoxy)phenyl]-2,4-pyrimidinediamine(R926705) In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to yield5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.83 (d, 1H, J=3.3 Hz), 7.81 (s, 1H), 7.50 (d, 2H,J=9.0 Hz), 7.29 (d, 1H, J=9.0 Hz), 7.22 (dd, 1H, J=2.4 and 8.7 Hz), 6.84(d, 2H, J=8.7 Hz), 6.56 (d, 1H, J=1.2 Hz), 4.64 (s, 2H), 4.56 (2q, 1H,J=5.7 Hz), 1.31 (d, 6H, J=6.0 Hz); ¹⁹F NMR (CD₃OD): - 47926; LCMS: ret.time: 21.03 min.; purity: 99 %; MS (m/e): 409 (MH⁺). 7.3.6205-Fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926707) In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediaminewas reduced with DIBALH to yield5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.37 (s, 1H), 9.17 (s, 1H), 9.12 (s, 1H), 8.06 (d,1H, J=3.9 Hz), 8.01 (d, 1H, J=1.8 Hz), 7.41-7.35 (m, 2H), 7.26 (d, 1H,J=8.1 Hz), 7.11-7.05 (m, 2H), 6.60 (s, 1H), 6.51 (dd, 1H, J=2.4 and 8.4Hz), 5.41 (t, 1H, J=6.0 Hz), 4.51 (d, 2H, J=5.7 Hz); LCMS: ret. time:16.21 min.; purity: 95 %; MS (m/e): 367 (MH⁺). 7.3.621 N4-(4-tert-Butyl)phenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine(R926728) In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,N4-(4-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBAL to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy) phenyl]-2,4-pyrimidinediamine. ¹H NMR (CDCl₃): δ7.94 (d, 1H, J=3.0 Hz), 7.54 (d,2H, J=9.0 Hz), 7.37 (d, 2H, J=8.4 Hz), 7.29-7.35 (m, 1H), 7.19-7.14 (m,2H), 7.06 (d, 1H, J=8.1 Hz), 6.82 (d, 1H, J=2.7 Hz), 6.57 (dd, 1H, J=2.4and 8.1 Hz), 4.04-4.00 (m, 2H), 3.93-3.89 (m, 2H), 1.33 (s, 9H); ¹⁹F NMR(CDCl₃): -47214; LCMS: ret. time: 22.39 min.; purity: 94 %; MS (m/e):397 (MH⁺). 7.3.6225-(Hydroxymethyl)-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926735) In a manner similar to the preparation ofN4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine,N4-(3-hydroxyphenyl)-5-methoxycarbonyl-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediaminewas reduced with DIBALH to yield5-(hydroxymethyl)-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.87 (s, 1H), 7.35 (t, 1H, J=1.5 Hz), 7.15-7.08 (m,5H), 6.57-6.50 (m, 2H), 4.56 (s, 2H), 3.92-3.86 (m, 2H), 3.84-3.79 (m,2H); LCMS: ret. time: 14.11 min.; purity: 89 %; MS (m/e): 369 (MH⁺).7.3.6235-Fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-isopropylphenyl)-2,4-pyrimidinediamineR940289 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminereacted with DIBALH to give5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.03 min.; purity: 93 %; MS (m/e): 382 (M⁺), 384(MH⁺); ¹H NMR (DMSO-d₆): δ9.36 (1H, s), 9.24 (1H, s), 8.20 (1H, d, J=4.2Hz), 7.85 (1H, d, J=8.5 Hz), 7.57 (1H, s), 7.41 (1H, s), 7.33 (1H, t,J=8.5 Hz), 7.17 (1H, t, J=8.5 Hz), 7.05 (1H, d, J=8.5 Hz), 6.56 (1H, dd,J=8.5 Hz, J=2 Hz) 4.94 (1H, t, J=12 Hz), 3.94 (2H, t, J=4.7 Hz), 3.76(2H, m), 2.95 (1H, sept, J=6.9 Hz), 1.28 (6H, dd, J=6.9 Hz, J=0.6Hz).7.3.624N4-(3-tert-Butylphenyl)-5-fluoro-N2-[(2-hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamineR940287 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediaminereacted with DIBALH to giveN4-(3-tert-butylphenyl)-5-fluoro-N2-[2-(hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamine.LCMS: retn, time: 23.15 min.; purity: 99 %; MS (m/e): 407 (MH⁺); 1H NMR(DMSO-d₆): δ9.34 (1H, s), 9.22 (1H, s), 8.18 (1H, d, J=3.9 Hz), 8.04(1H, s), 8.00 (1H, d, J=8.7 Hz), 7.60 (1H, t, J=2.1 Hz), 7.47 (2H, m),7.34 (1H, t, J=7.8 Hz), 7.21 (1H, d, J=8.7 Hz), 6.69 (1H, s), 5.54 (1H,t, J=5.8 Hz), 4.63 (2H, d, J=5.8 Hz), 1.35 (9H, s). 7.3.6255-Fluoro-N4-(3-isopropylphenyl)-N2-[(2-hydroxymethylene]benzofur-5-yl]-2,4-pyrimidinediamineR940286 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediaminereacted with DIBALH to give5-fluoro-N4-(3-isopropylphenyl)-N2-[(2-hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 21.93 min.; purity: 99 %; MS (m/e): 393 (MH⁺); ¹H NMR(DMSO-d₆): δ9.33 (1H, s), 9.23 (1H, s), 8.18 (1H, d, J=3.9 Hz), 8.03(1H, s), 7.86 (1H, d, J=7.1 Hz), 7.57 (1H, s), 7.49 (2H, m), 7.33 (1H,t, J=7.1 Hz), 7.05 (1H, d, J=7.1 Hz), 6.69 (1H, s), 5.54 (1H, t, J=5.7Hz), 4.63 (2H, d, J=5.7 Hz), 2.90 (1H, sept, J=6.9 Hz), 1.26 (6H, d,J=6.9 Hz). 7.3.626N4-(3-tert-Butylphenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamineR940282 In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminereacted with DIBALH to giveN4-(3-tert-butylphenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 21.63 min.; Purity: 98 %; MS (m/e): 396 (M⁺). 7.3.627N4-[3,4-Bis(hydroxymethyl)phenyl]-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940292) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,N2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-[6-(3,3-dihydroisobenzofuranyl-1-one)]-5-fluoro-2,4-pyrimidinediaminereacted with DIBALH to giveN4-[3,4-bis(hydroxymethyl)phenyl]-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine.LCMS: retn, time: 13.06 min.; purity: 100 %; MS (m/e): 400 (M⁺). 7.3.628(R935149):N2-(3,4-Ethylenedioxyphenyl)-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine2-Chloro-5-fluoro-N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediaminewas reduced with 10 eq. DIBALH (1.0 M in toluene) at 0 ⁰C indichloromethane. Reaction was quenched with methanol, diluted withethylacetate followed by the addition of aqueous Rochelle′s saltsolution, stirred at room temperature for 30 minutes followed by theaddition of anhydrous sodium sulfate. The solution was filtered throughCelite, concentrated and purified the concentrated by silica gel columnchromatography to furnish theN2-(3,4-ethylenedioxyphenyl)-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.01 (br s, 1H), 9.6 (br s, 1H), 8.13 (d, 1H, J=4.7Hz), 7.58 (d, 2H, J=8.2 Hz), 7.31 (d, 2H, J=8.8 Hz), 7.18 (d, 1H, J=2.3Hz), 6.88 (dd, 1H, J=2.3 and 8.8 Hz), 6.73 (d, 1H, J=8.8 Hz), 4.21-4.19(m, 4H), 3.56 (br s, 2H), 1.20 (s, 6H); LCMS: ret. time: 20.34 min.;purity: 98%; MS (m/e): 411 (MH⁺). 7.3.629 (R935151):5-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.89 (d, 1H, J=2.9 Hz), 7.46 (d, 3H, J=8.8 Hz), 7.27(d, 2H, J=8.2 Hz), 6.89 (d, 2H, J=9.3 Hz), 6.68-6.65 (m, 1H), 4.53(septet, 1H, J=5.8 Hz), 3.57 (s, 2H), 1.36 (d, 6H, J=5.8 Hz), 1.31 (s,6H); LCMS: ret. time: 23.43 min.; purity: 99%; MS (m/e): 411 (MH⁺).7.3.630 (R935153):5-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine:In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.89 (d, 1H, J=2.9 Hz), 7.57 (s, 1H), 7.41 (d, 2H,J=8.8 Hz), 7.29 (d, 2H, J=8.2 Hz), 7.16 (d, 1H, J=8.2 Hz), 7.10 (d, 1H,J=8.8 Hz), 6.80-6.55 (m, 2H), 5.58 (s, 2H), 1.30 (s, 6H); LCMS: ret.time: 18.01 min.; purity: 98%; MS (m/e): 369 (MH⁺). 7.3.631 (R935154):N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.88 (d, 1H, J=3.8 Hz), 7.34 (t, 1H, J=2.3 Hz), 7.19(dd, 1H, J=2.3 and 8.2 Hz), 7.14 (d, 1H, J=7.6 Hz), 7.01-6.97 (m, 2H),6.84 (d, 1H, J=8.8 Hz), 6.53 (dd, 1H, J=1.7 and 7.6 Hz), 4.26 (s, 4H),3.98 (t, 2H, J=4.1 Hz), 3.89 (t, 2H, J=4.1 Hz); LCMS: ret. time: 18.36min.; purity: 99%; MS (m/e): 399 (MH⁺). 7.3.632 (R935155):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine:In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediaminewas reduced to5-fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith DIBALH. ¹H NMR (CDCl₃): δ7.73 (d, 1H, J=3.5 Hz), 7.33 (d, 2H, J=8.8Hz), 7.15 (br s, 1H), 7.04 (app t, 2H, J=8.2 and 7.6 Hz), 6.78 (d, 2H,J=8.8 Hz), 6.49 (d, 1H, J=7.6 Hz), 3.95 (t, 2H, J=4.7 Hz), 3.80 (t, 2H,J=4.7 Hz); LCMS: ret. time: 14.49 min.; purity: 98%; MS (m/e): 357(MH⁺). 7.3.633 (R935156):5-Fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(4-isopropoxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.90 (d, 1H, J=3.5 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.34(t, 1H, J=2.3 Hz), 7.13 (t, 1H, J=8.2 Hz), 6.93 (m, 3H), 7.76 (d, 1H,J=2.3 Hz), 6.52 (dd, 1H, J=2.3 and 8.2 Hz), 4.52 (septet, 1H, J=5.7 Hz),3.95-3.85 (m, 4H), 1.34 (d, 6H, J=5.7 Hz); LCMS: ret. time: 21.17 min.;purity: 98%; MS (m/e): 399 (MH⁺). 7.3.634 (R935158):5-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[4-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine:In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[4-[1-ethoxycarbonyl1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to give5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[4-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.83 (d, 1H, J=3.5 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.35(d, 2H, J=8.8 Hz), 7.31 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.8 Hz), 4.03(t, 2H, J=4.7 Hz), 3.89 (t, 2H, J=4.7 Hz), 3.56 (s, 2H), 1.30 (s, 6H);LCMS: ret. time: 16.86 min.; purity: 96%; MS (m/e): 413 (MH⁺). 7.3.635(R935160):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine:In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(4-isopropoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to give5-fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.12 (s, 1H), 8.92 (s, 1H), 7.98 (d, 1H, J=3.5 Hz),7.59 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=9.3 Hz), 6.86 (d, 2H, J=8.8 Hz),6.76 (d, 2H, J=9.3 Hz), 4.82 (t, 1H, J=4.9 Hz), 4.55 (septet, 1H, J=6.4Hz), 3.89 (t, 2H, J=5.3 Hz), 3.67 (app q, 2H, J=5.3 and 4.9 Hz), 1.24(d, 6H, J=6.4 Hz); LCMS: ret. time: 19.56 min.; purity: 100%; MS (m/e):399 (MH⁺). 7.3.636 (R935161):5-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[4-(1-ethoxycarbonyl-1-methyl)ethylphenyl]-5-fluoro-N2-(3-methoxycarbonylmethylphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to give5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.27 (s, 1H), 9.11 (s, 1H), 8.07 (d, 1H, J=3.5 Hz),7.67 (d, 2H, J=8.8 Hz), 7.38-7.24 (m, 4H), 7.06 (t, 1H, J=8.2 Hz), 6.46(dd, 1H, J=8.2 Hz), 4.83 (t, 1H, J=5.3 Hz), 4.66 (t, 1H, J=5.3 Hz), 3.88(t, 2H, J=5.3 Hz), 3.67 (t, 1H, J=5.3 Hz), 3.66 (t, 1H, J=5.3 Hz), 3.38(d, 2H, J=5.3 Hz), 1.20 (s, 6H); LCMS: ret. time: 17.17 min.; purity:96%; MS (m/e): 413 (MH⁺). 7.3.637 (R935168):5-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[4-(1-ethoxycarbonyl-1-methyl)ethylphenyl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to produce 5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.21 (s, 1H), 8.93 (s, 1H), 8.00 (d, 1H, J=4.1 Hz),7.62 (d, 2H, J=8.8 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.27 (d, 2H, J=8.8 Hz),6.75 (d, 2H, J=8.8 Hz), 4.65 (t, 1H, J=5.3 Hz), 4.47 (septet, 1H, J=5.8Hz), 3.38 (d, 2H, J=5.3 Hz), 1.22 (d, 6H, J=5.8 Hz), 1.20 (s, 6H); LCMS:ret. time: 22.97 min.; purity: 99%; MS (m/e): 411 (MH⁺). 7.3.638(R935170):5-Fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine:In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to produce 5-fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.23 (s, 1H), 9.14 (s, 1H), 9.06 (s, 1H), 8.07 (d,1H, J=4.1 Hz), 7.51 (dd, 1H, J=1.7 and 7.6 Hz), 7.30 (app t, 1H, J=2.3and 1.7 Hz), 7.19 (t, 1H, J=8.2 Hz), 7.13 (br s, 1H), 7.11 (m, 1H), 6.96(t, 1H, J=7.6 Hz), 6.61 (dd, 1H, J=2.3 and 8.2 Hz), 6.28 (dd, 1H, J=2.3Hz and 8.2 Hz), 4,84 (t, 1H, J=5.8 Hz), 3.92 (t, 2H, J=5.2 Hz), 3.68(app qt, 2H, J=5.2 Hz); LCMS: ret. time: 14.71 min.; purity: 96%; MS(m/e): 357 (MH⁺). 7.3.639 (R935171):5-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)--2,4-pyrimidinediamine In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-pyrimidine-2,4-diamine,N4-[4-(1-ethoxycarbonyl-1-methyl)ethyl)phenyl]-5-fluoro-N2-(3-hydoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to give5-fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.24 (s, 1H), 9.13 (s, 1H), 9.01 (s, 1H), 8.04 (d,1H, J=3.5 Hz), 7.68 (d, 2H, J=8.8 Hz), 7.29 (d, 2H, J=8.8 Hz), 7.16 (brs, 1H), 7.07 (m, 1H), 6.94 (t, 1H, 8.8 Hz), 6.30 (m, 1H), 4.64 (t, 1H,J=5.8 Hz), 3.38 (d, 2H, J=5.3 Hz), 1.20 (s, 6H); LCMS: ret. time: 17.36min.; purity: 100%; MS (m/e): 369 (MH⁺). 7.3.640 (R935174):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-(2-carbomethoxybenzofur-5-yl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2[4-(2-hydroxyethoxy)phenyl]-N2-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.26 (s, 1H), 8.94 (s, 1H), 8.01 (d, 1H, J=4.1 H),7.99 (s, 1H), 7.52-7.45 (m, 4H), 6.72 (d, 2H, J=9.3 Hz), 6.66 (s, 1H),5.46 (t, 1H, J=5.3 Hz), 4.82 (t, 1H, J=5.8 Hz), 4.55 (d, 2H, J=5.8 Hz),3.89 (t, 2H, J=5.3 Hz), 3.67 (app qt, 2H, J=5.3 Hz); LCMS: ret. time:14.97 min.; purity: 91%; MS (m/e): 411 (MH⁺). 7.3.641 (R935176):N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine:In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-methoxycarbonylmethyleneoxypheny)-2,4-pyrimidinediaminewas reduced with DIBALH to provideN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.22 (s, 1H), 8.98 (s, 1H), 8.05 (d, 1H, J=3.5 Hz),7.47 (dd, 1H, J=1.1 and 8.2 Hz), 7.27 (t, 1H, J=1.7 Hz), 7.23 (d, 1H,J=2.3 Hz), 7.18 (t, 1H, J=8.2 Hz), 7.05 (dd, 1H, J=2.3 and 8.8 Hz), 6.68(d, 1H, J=8.2 Hz), 6.61 (dd, 1H, J=1.7 and 8.8 Hz), 4.85 (t, 1H, J=5.3Hz), 4.18-4.14 (m, 4H), 3.91 (t, 2H, J=5.3 Hz), 3.68 (qt, 2H, J=5.3 Hz);LCMS: ret. time: 17.35 min.; purity: 92%; MS (m/e): 399 (MH⁺). 7.3.642(R935177):5-Fluoro-N2-[4-(2-hydroxy-1,1,dimethylethyl)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(2-carbomethoxybenzofur-5-yl)-N2-[4-(1-ethoxycarbonyl-1-methyl)ethylphenyl]-5-fluoro-2,4-pyrimidinediaminewas reduced with DIBALH to produce 5-fluoro-N2-[4-(2-hydroxy-1,1,dimethylethyl)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 18.17 min.; purity: 94%; MS (m/e): 423 (MH⁺). 7.3.643(R935178):5-Fluoro-N2-[3-(2-hydroxyethyloxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(2-carbomethoxybenzofur-5-yl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[3-(2-hydroxyethyloxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.93 (s, 1H), 9.12 (s, 1H), 8.07 (d, 1H, J=3.6 Hz),8.01 (d, 1H, J=2.3 Hz), 7.55-7.46 (m, 2H), 7.29 (br s, 1H), 7.23 (d, 1H,J=8.2 Hz), 7.03 (t, 1H, J=8.2 Hz), 6.68 (s, 1H), 6.44 (dd, 1H, J=2.3 and8.2 Hz), 5.47 (t, 1H, J=5.8 Hz), 4.80 (t, 1H, J=5.3 Hz), 4.55 (d, 2H,J=5.3 Hz), 3.81 (qt, 2H, J=5.3 Hz), 3.63 (qt, 2H, J=5.3 Hz); LCMS: ret.time: 15.41 min.; purity: 88%; MS (m/e): 411 (MH⁺). 7.3.644 (R935181):N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-imidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3,5-dimethoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidineaminewas reduced with DIBALH to giveN4-(3,5-dimethoxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine:¹H NMR (DMSO-d₆):δ9.24 (s, 1H), 9.18 (s, 1H), 8.11 (d, 1H, J=3.5 Hz),7.31-7.26 (m, 2H), 7.05 (d, 1H, J=8.2 Hz), 6.99 (d, 1H, J=2.3 Hz), 6.43(dd, 1H, J=2.3 Hz, 8.2 Hz), 6.20 (t, 1H, J=2.3 Hz), 4.80 (t, 1H, J=5.8Hz), 3.83 (t, 2H, J=5.3 Hz), 3.67 (s, 6H), 3.66-3.60 (m, 2H); LCMS: ret.time: 18.78 min.; purity: 95%; MS (m/e): 400 (MH⁺). 7.3.645 (R935183):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBAL-H to provide5-fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.H NMR (DMSO-d₆): δ9.15 (s, 1H), 8.97 (s, 1H), 8.00 (d, 1H, J=3.5 Hz),7.49 (d, 2H; J=8.8 Hz), 7.40-7.31 (m 2H), 6.88 (d, 1H, J=8.8 Hz), 6.80(d, 2H, J=8.8 Hz), 4.82 (t, 1H, J=5.3 Hz), 4.12-4.04 (m 4H), 3.90 (t,2H, J=5.2 Hz), 3.70-3.65 (app qt, 2H, J=5.3 Hz), 2.07 (q, 2H, J=5.3 Hz);LCMS: ret. time: 17.05 min.; purity: 96%; MS (m/e): 413 (MH⁺). 7.3.646(R935186):5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediaminewas reduced with DIBALH to provide5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.21 (s, 1H), 9.14 (s, 1H), 8.07 (d, 1H, J=3.5 Hz),7.42-7.36 (m, 2H), 7.29-7.24 (m, 2H), 7.07 (t, 1H, J=8.2 Hz), 6.90 (d,1H, J=8.8 Hz), 6.45 (dd, 1H, J=1.7 and 8.3 Hz), 4.82 (t, 1H, J=5.3 Hz),4.12-4.04 (app q, 2H, J=5.3 Hz), 3.86 (t, 2H, J=5.3 Hz), 3.67 (app qt,2H, J=5.3 Hz), 2.07 (q, 2H, J=5.3 Hz); LCMS: ret. time:17.95 min.;purity: 96%; MS (m/e): 413 (MH⁺). 7.3.647 N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine (R926720) The reaction of N2-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamineand lithium hydroxide(LiOH) in THF:H₂O at room temperature gaveN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ10.01 (bs, 1H), 9.69 (bs, 1H),8.13 (d, 1H, J=4.8 Hz), 7.57 (d, 2H, J=8.7 Hz), 7.50 (s, 1H), 7.35 (d,2H, J=8.1 Hz), 7.13 (d, 1H, J=8.7 Hz), 6.75 (d, 1H, J=9.0 Hz), 5.21 (dd,1H, J=6.3 and 10.5 Hz), 3.49 (dd, 1H, J=10.5 and 16.5 Hz), 3.17 (dd, 1H,J=6.6 and 16.5 Hz), 1.27 (s, 9H); LCMS: ret. time: 22.53 min.; purity:93 %; MS (m/e): 423 (MH⁺). 7.3.648N4-(4-tert-Butylphenyl)-N2-(3-carboxymethyleneoxyphenyl)-5-fluor-2,4-pyrimidinediamine(R926726) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,N4-(4-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand lithium hydroxide were reacted to yieldN4-(4-tert-butylphenyl)-5-fluoro-N2-(3-carboxymethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.88 (bs, 1H), 9.29 (s, 1H), 9.16 (s, 1H), 8.07 (d,1H, J=3.3 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.35-7.31 (m, 3H), 7.26 (d, 1H,J=8.4 Hz), 7.06 (t, 1H, J=8.4 Hz), 6.41 (dd, 1H, J=2.4 and 8.4 Hz), 4.54(s, 2H), 1.27 (s, 9H); ¹⁹F NMR (DMSO-d₆): - 46463; LCMS: ret. time:22.94 min.; purity: 97 %; MS (m/e): 411 (MH⁺). 7.3.6495-Fluoro-N2-[3-(carboxymethyleneoxy)phenyl]-N4-[4-(isopropoxy)phenyl]-2,4-pyrimidinediamine (R926731) In a mannersimilar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamineand lithium hydroxide were reacted to yield5-fluoro-N2-(3-carboxymethyleneoxyphenyl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ6.19 (bs, 1H), 9.01 (s, 1H), 8.02 (d, 1H, J=3.9 Hz),7.63 (d, 2H, J=9.3 Hz), 7.19-7.14 (m, 2H), 6.96 (t, 1H, J=8.7 Hz), 6.87(d, 2H, J=9.6 Hz), 6.28 (dd, 1H, J=2.45 and 9.0 Hz), 4.56 (2q, 1H, J=6.6Hz), 3.94 (s, 2H), 1.24 (d, 6H, J=6.6 Hz); LCMS: ret. time: 20.13 min.;purity: 100 %; MS (m/e): 413 (MH⁺). 7.3.650N2,N4-Bis(4-carboxymethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine(R926560) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,thehydrolysis ofN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith LiOH gaveN2,N4-bis(4-carboxymethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine ¹HNMR (CD₃OD): δ7.86 (bs, 1H), 7.55 (d, 2H, J=9.0 Hz), 7.32 (bd, 2H, J=9.3Hz), 6.95 (m, 4H), 4.66 (s, 2H), ¹⁹F NMR (CDCl₃): - 21852; LCMS: ret.time: 15.16 min.; purity: 77%; MS (m/e): 429 (MH⁺). 7.3.651N2-(3-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926483) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,thereaction ofN2-(3-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith LiOH gaveN2-(3-carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.90 (s, 1H), 9.20 (s, 2H), 8.05 (d, 1H, J=1.2 Hz),7.32-7.21 (m, 3H), 7.08 (t, 1H, J=8.1 Hz), 6.80 (d, 1H, J=8.4 Hz), 6.40(dd, 1H, J=1.8 and 8.2 Hz), 4.53 (s, 2H), 4.20 (s, 4H); LCMS: ret. time:18.26 min.; purity: 100%; MS (m/e): 413 (MH⁺). 7.3.652N2-(3-Carboxymethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945126) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith LiOH gaveN2-(3-carboxymethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine^(. 1)HNMR (DMSO-d₆): δ4.55 (s, 2H), 6.43 (dd, J=2.1, 8.1 Hz, 1H), 6.48 (dd,J=2.1 and 7.2 Hz, 1H), 7.06-7.13 (m, 3H), 7.28-7.34 (m, 3H), 8.09 (d,J=3.6 Hz, 1H), 9.22 (br, 1H), 9.28 (br, 1H), 9.34 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ- 163.85; LCMS: ret. time: 15.88 min.; purity: 100%; MS(m/e): 370.63 (MH⁺). 7.3.653N2-(4-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926238) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,the reaction ofN2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith LiOH gaveN2-(carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.16 (d, 1H, J=4.8 Hz), 7.37 (bd, 2H, J=9 Hz), 7.259d, 1H, J=3Hz), 7.08 (m, 1H), 6.83 (m, 3H), 4.64 (s, 2H), 4.23 (s, 4H);LCMS: ret. time: 19.15 min.; purity: 100%; MS (m/e): 413 (MH⁺). 7.3.654N2-(4-Carboxymethyleneoxyphenyl)-5-Fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926564) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineupon treatment with LiOH gave5-fluoro-N2-(4-carboxymethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.89 (d, 1H, J=5.1 Hz), 7.34 (dd, 2H, J=2.1 and 9.3Hz), 7.19-7.08 (m, 2H), 6.98 (dd, 2H, J=2.4 and 8.4 Hz), 6.69 (m, 1H),4.68 (s, 2H); ¹⁹F NMR (CD₃OD): - 21860; LCMS: ret. time: 15.69 min.;purity: 99%; MS (m/e): 371 (MH⁺). 7.3.655N2-(2-Carboxybenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926478) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-4-pyrimidinediamineupon LiOH treatment gaveN2-(2-carboxybenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.97 (bd, 2H), 7.60-7.44 (m, 4H), 7.20-7.05 (m, 3H),6.69 (bd, 1H); ¹⁹F NMR (CD₃OD): - 21844; LCMS: ret. time: 16.77 min.;purity: 100%; MS (m/e): 381 (MH⁺). 7.3.656N2-(2-Carboxyindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926479) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineupon LiOH treatment gaveN2-(2-carboxyindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.83 (m, 1H), 7.73 (s, 1H), 7.50 (bd, 1H, J=8.7 Hz),7.30-7.11 (m, 5H), 6.68 (bd, 1H); LCMS: ret. time: 16.50 min.; purity:97%; MS (m/e): 380 (MH⁺). 7.3.657N4-(4-tert-Butylphenyl)-N2-(2-carboxybenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R926481) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,LiOH treatment withN4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminegaveN4-(4-tert-butylphenyl)-N2-(2-carboxybenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ9.3 (bd, 2H), 8.25 (s, 1H), 8.10 (s, 1H), 7.65-7.30 (m,5H), 1.25 (s, 9H); ¹⁹F NMR (CD₃OD): - 21844; LCMS: ret. time: 23.32min.; purity: 100%; MS (m/e): 421 (MH⁺). 7.3.658N4-(3-tert-Butylphenyl)-N2-[3-carboxymethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamineR940280 In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas reacted with LiOH to giveN4-(3-tert-butylphenyl)-N2-(3-carboxymethyleneoxyphenyl)-5-fluoro2,4-pyrimidinediamine. LCMS: ret. time: 23.61 min.; purity: 99 %; MS(m/e): 410 (M⁺), 412 (MH⁺); ¹H NMR (DMSO-d₆): δ9.45 (1H, s), 9.33 (1H,s), 8.21 (1H, d, J=3.9 Hz), 7.98 (1H, d, J=6.6 Hz), 7.60 (1H, t, J=2Hz), 7.44-7.34 (3H, m), 7.24-7.15 (2H, m), 6.54 (1H, d, J=7.8 Hz), 4.68(2H, s), 1.36 (9H, s). 7.3.659N2-(3-Carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950190) The reaction ofN2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(0.1 g) and LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h atroom temperature followed by treatement with aqueous HCl gave the solid.The resulting solid was filtered, washed with water and dried to giveN2-(3-carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 18.23 min.; purity: 87.6%; MS (m/e): 412.01 (MH⁺).7.3.660N2-(Carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethyloxy)phenyl]-2,4-pyrimidinediamine(R950230) In a manner similar to the preparation ofN2-(3-carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,the hydrolysis ofN2-(ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylenoxy)phenyl]-2,4-pyrimidinediaminewith LiOH gaveN2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethyloxy)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.15 min.; purity: 78.3%; MS (m/e): 413.01 (MH⁺).7.3.6615-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950231) A mixture ofN2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(10 mg), 2-aminoethanol (10 equiv.) and PyBroP (2 equiv.) was stirred in0.5 ml DMF for 24 hours at room temperature. The mixture was dilutedwith water, extracted with EtOAc and the organic phase was dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas subjected to column chromatography on silica gel (CHCl₃:Acetone,2:1) to give5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 12.98 min.; purity:92.6%; MS (m/e): 455.97 (MH⁺). 7.3.662N2-[3-(N-2-Aminoethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylenoxy)phenyl]-2,4-pyrimidinediamine(R950232) In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand 1,2-ethylenediamine were reacted to affordN2-[3-(N-2-aminoethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylenoxy)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 11.31 min.; purity: 93.6%; MS (m/e): 454.94 (MH⁺).7.3.6635-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950233) In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand methylamine were reacted to give5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 14.93 min.; purity: 92.9%; MS (m/e): 426.27 (MH⁺).7.3.6645-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine (R950234) In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand N-methylethylenediamine were reacted to give5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time:11.39 min.; purity: 97.7%; MS (m/e): 468.96 (MH⁺). 7.3.665N2-[3-[N-(2-N-Benzylamino)ethylamino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(R950235) In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand N-benzylethylenediamine were reacted to giveN2-[3-[N-(2-N-benzylamino)ethylamino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 14.39 min.; purity: 97.3%; MS (m/e): 545.01 (MH⁺).7.3.6665-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950236) In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand morpholine were reacted to afford5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 15.24 min.; purity: 94.6xx%; MS (m/e): 482.40 (MH⁺).7.3.667 N2-[3-(3-N,N-Dimethylaminopropyl)aminocarbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(R950237) In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand N,N-dimethylpropanediamine were reacted to giveN2-[3-(3-N,N-Dimethylaminopropyl)aminocarbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 13.33 min.; purity: 91.4%; MS (m/e): 497.47 (MH⁺).7.3.668 N2-[3-[N-(2,3-Dihydroxypropyl)amino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine(R950238) In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand 1-amino-2,3-propanediol were reacted to giveN2-[3-[N-(2,3-dihydroxypropyl)amino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 12.86 min.; purity: 90.0%; MS (m/e): 486.40 (MH⁺).7.3.6695-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine(R950239) In like manner to the preparation ofN4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand 4-(2-aminoethyl)morpholine were reacted to give5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time:13.52 min.; purity: 92.4%; MS (m/e): 525.47 (MH⁺). 7.3.6702,4-Bis[N-(L)-tyrosine methyl ester]-5-ethoxycarbonylpyrimidine(R926514) and 5-Ethoxycarbonyl-2-methoxy-4-[N-(L)-tyrosine methylester]pyrimidine (R926513) A mixture of tyrosine methyl ester (58 mg,0.3 mmol), 2,4-dichloro-5-ethoxycarbonylpyrimidine (44 mg, 0.1 mmol) inMeOH (2mL) was heated in a sealed tube at 100° C. for a period ofovernight, diluted with H₂O (20 mL), acidified with 2N HCl and extractedwith ethyl acetate (3 × 25 mL). The solvent was evaporated and theresidue was purified by preparative TLC using 30% EtOAc/Hexanes toobtain a mixture of 2,4-bis[N-(L)-tyrosine methylester]-5-ethoxycarbonylpyrimidine (R926514). ¹H NMR (CDCl₃): δ8.60 (1H,J=6.6 Hz), 8.36 (s, 1H), 7.05 (d, 2H, J=8.7 Hz), 6.84 (d, 2H, J=8.1 Hz),6.74 (d, 2H, J=9 Hz), 6.54 (d, 2H, J=9 Hz), 4.82 (t, 2H, J=6 Hz), 4.25(q, 2H, J=6.3 Hz), 3.73 (s, 3H), 3.72 (s, 3H), 3.06 (m, 4H), 1.31 (t,3H, J=7.2 Hz) and 5-ethoxycarbonyl-2-methoxy-4-[N-(L)-tyrosine methylester]pyrimidine (R926513): ¹H NMR (CDCl₃): δ8.78 (s, 1H), 8.65 (d, 1H,J=6.9 Hz), 7.02 (dd, 2H, J=2.1 and 6.3 Hz), 6.77 (dd, 2H, J=2.4 and 6.6Hz), 4.93 (q, 1H, J=1.5 and 6.9 Hz), 4.30 (q, 2H, J=8.1 Hz), 3.90 (s,3H), 3.70 (s, 3H), 3.17 (dd, 1H, J=5.4 Hz), 3.06 (dd, 1H, J=7.5 and 7.8Hz), 1.33 (t, 3H, J=6.9 Hz); LCMS: ret. time: 22.58 min.; purity: 99%;MS (m/e): 376 (M⁺). 7.3.671N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926252) In like manner to the preparation of N2,N4-bis[N-(L)-tyrosinemethyl ester]-5-ethoxycarbonylpyrimidine, the reaction of2,4-dichloro-5-ethoxycarbonylpyrimidine with 3,4-ethylenedioxyanilinegaveN2,N4-bis(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.01 (s, 1H), 9.65 (bs, 1H), 8.62 (s, 1H), 7.18 (bs,2H), 7.04 (dd, 1H, J=1.8 and 8.7 Hz), 6.93 (d, 1H, J=7.5 Hz), 6.76 (d,1H, J=8.7 Hz), 6.65 (d, 1H, J=8.7 Hz), 4.28 (q, 2H, J=6.9 Hz), 1.31 (t,3H, J=7.2 Hz); LCMS: ret. time: 27.25 min.; purity: 100%; MS (m/e): 451(MH⁺). 7.3.672N2,N4-Bis(4-hoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926253) In like manner to the preparation of N2,N4-bis[N-(L)-tyrosinemethyl ester]-5-ethoxycarbonylpyrimidine, the reaction of2,4-dichloro-5-ethoxycarbonylpyrimidine with ethyl 4-aminophenoxyacetategaveN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine(R926253).¹H NMR (CD₃OD): δ8.60 (bs, 1H), 7.4 (bs, 1H), 7.33 (d, 4H, J=9Hz), 6.94(bd, 4H), 4.76 (s, 2H), 4.75 (s, 2H), 4.44 (q, 2H, J=6.9 Hz), 3.79 (s,3H), 1.40 (t, 3H, J=6.9 Hz); LCMS: ret. time: 25.83 min.; purity: 89%;MS (m/e): 511 (MH⁺). 7.3.673 2,4-Bis[N-(L)-phenylalaninyl ethylester]-5-ethoxycarbonylpyrimidine (R926526) In like manner to thepreparation of N2,N4-bis[N-(L)-tyrosine methylester]-5-ethoxycarbonylpyrimidine, the reaction of2,4-dichloro-5-ethoxycarbonylpyrimidine with ethyl (L)-phenylalanineethyl ester in MeOH or EtOAc gave 2,4-bis[N-(L)-phenylalanine ethylester]-5-ethoxycarbonylpyrimidine. ¹H NMR (CDCl₃): δ8.55 (d, 1H, J=7.2Hz), 8.51 (s, 1H), 7.35-7.10 (m, 10H), 5.88 (d, 1H, J=J=6 Hz), 4.88(ddd, 1H, J=6.3 Hz), 4.80 (ddd, 1H, J=6.3 Hz), 4.23 (q, 2H, J=7.2 Hz),4.12 (q, 4H, J=7.2 Hz), 3.65 (t, 2H, J=6 Hz), 3.56 (t, 2H, J=6.0 Hz),1.30 (t, 2H,, J=6 Hz), 1.30 (t, 3H, J=7.2 Hz), 1.20 (m, 6H); LCMS: ret.time: 32.22 min.; purity: 89%; MS (m/e): 535 (MH⁺). 7.3.6742,4-Bis[N-(L)-valinyl ethyl ester]-5-ethoxycarbonylpyrimidine (R926527)In like manner to the preparation of N2,N4-bis[N-(L)-tyrosine methylester]-5-ethoxycarbonylpyrimidine, the reaction of2,4-dichloro-5-ethoxycarbonylpyrimidine with ethyl (L)-valine ethylester in MeOH or EtOAc gave 2,4-bis[N-(L)-valinyl ethylester]-5-ethoxycarbonylpyrimidine. ¹H NMR (CDCl₃): δ8.59 (d, 1H, J=7.8Hz), 8.56 (s, 1H), 5.69 (d, 1H, J=8.7 Hz), 4.62 (m, 1H), 4.51 (m, 1H),4.25 (q, 2H, J=7.5 Hz), 4.20 (m, 4H), 2.20 (m, 2H), 1.34 (t, 3H, J=7.8Hz), 1.27 (t, 6H, J=7.5 Hz), 1.00 (m, 12H); LCMS: ret. time: 29.27 min.;purity: 97%; MS (m/e): 439 (MH⁺). 7.3.6755-Ethoxycarbonyl-N2-(3-hydroxyphenyl)-4-[N-(L)-phenylalanine ethylester]-2-pyrimidineamine (R926528) The reaction of2-chloro-N4-(3-hydroxyphenyl)-5-ethoxycarbonylpyrimidineamine with 3equivalents of (L)-N-phenylalanine ethyl ester in methanol at 80-100° C.for 24 h followed by dilution with water and acidification with 2N HClhave the acidic solution. The resulting solution was extracted withEtOAc and the residue was purified by silics gel column chromatographyto afford 4-[N-(L)-phenylalanine ethylester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine. ¹H NMR(CDCl₃): δ9.4 (bs, 1H), 9.13 (d, 1H, J=6 Hz), 8.45 (bs, 1H), 7.59 (s,1H), 7.34-7.25 (m, 5H), 7.15 (t, 1H, J=8.1 Hz), 6.73 (bd, 1H, J=7.5 Hz),6.67 (dd, 1H, J=1.8 and 7.8 Hz), 4.86 (dt, 1H, J=3 and 5.1 Hz), 4.32 (q,2H, J=6.3 Hz), 4.19 (q, 2H, J=7.2 Hz), 3.30 (dd, 1H, J=4.8 and 8.7 Hz),3.18 (dd, 1H, J=5.1 and 8.7 Hz), 1.36 (t, 3H, J=6.9 Hz), 1.65 (t, 3H,J=7.2 Hz); LCMS: ret. time: 27.49 min.; purity: 91%; MS (m/e): 451(MH⁺). 7.3.676N2-(3,4-Ethylenedioxyphenyl)-5-ethoxycarbonyl-4-[N-(L)-phenyl glycinylethyl ester)-2-pyrimidineamine (R926536) In like manner to thepreparation of 4-[N-(L)-phenylalanine ethylester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine, thereaction of 2-chloro-5-ethoxycarbonyl-4-[N-(L)-phenyl glycinyl ethylester)pyrimidine with 3,4-ethylenedioxyaniline in MeOH or EtOAc gaveN2-(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-4-[N-(L)-phenyl glycinylethyl ester]-2-pyrimidineamine. ¹H NMR (CDCl₃): δ9.15 (s, 1H), 8.9 (s,1H), 8.61 (s, 1H), 7.48 (m, 2H), 7.38 (m, 3H), 7.16 (bs, 1H), 6.80 (m,2H0, 5.75 (d, 1H), 4.24 (m, 6H), 3.66 (s, 3H), 1.35 (t, 3H); LCMS: ret.time: 28.16 min.; purity: 85%; MS (m/e): 465 (MH⁺). 7.3.677N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926579) In like manner to the preparation of 4-[N-(L)-phenylalanineethyl ester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine,the reaction ofN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-ethoxycarbonyl-4-pyrimidineaminewith methyl 4-aminophenoxyacetate gaveN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ10.17 (s, 1H), 8.73 (s, 1H), 8.45 (bs, 1H), 7.49 (d,2H, J=8.7 Hz), 7.43 (d, 2H, J=8.7 Hz), 7.33 (bs, 1H), 6.87 (d, 2H, J=6Hz), 6.84 (d, 2H, J=5.7 Hz), 4.63 (s, 2H), 4.53 (s, 2H), 4.33 (q, 2H,J=6.9 Hz), 3.81 (s, 3H), 1.49 (s, 9H), 1.39 (t, 3H, J=7.5 Hz); LCMS:ret. time: 27.93 min.; purity: 96%; MS (m/e): 553 (MH⁺). 7.3.678N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-5-methoxycarbonyl-2,4-pyrimidinediamine(R926580) In like manner to the preparation of 4-[N-(L)-phenylalanineethyl ester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine,the reaction ofN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-ethoxycarbonyl-4-pyrimidineaminewith methyl 4-aminophenoxyacetate gaveN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-methoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.5-methyl ester was obtained due to the cross esterification reaction inMeOH. ¹H NMR (CDCl₃): δ10.13 (s, 1H), 8.73 (s, 1H), 8.45 (bs, 1H), 7.49(d, 2H, J=8.7 Hz), 7.43 (d, 2H, J=8.7 Hz), 7.33 (bs, 1H), 6.87 (m, 4H),4.63 (s, 2H), 4.53 (s, 2H), 4.33 (q, 2H, J=6.9 Hz), 3.88 (s, 3H), 3.81(s, 3H), 1.49 (s, 9H); LCMS: ret. time: 27.43 min.; purity: 100%; MS(m/e): 539 (MH⁺). 7.3.679N4-(4-Carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926583) The treatment ofN4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith trifluoroacetic acid in THF:H₂O at room temperature affordedN4-(4-carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.03 (s, 1H), 8.65 (s, 1H), 7.49 (bd, 4H, J=8.7 Hz),6.89 (d, 2H, J=9.3 Hz), 6.81 (d, 2H, J=8.1 Hz), 4.70 (s, 2H), 4.65 (s,2H), 4.33 (q, 2H, J=6.9 Hz), 3.81 (s, 3H), 1.49 (s, 9H), 1.39 (t, 3H,J=7.5 Hz); LCMS: ret. time: 22.28 min.; purity: 73%; MS (m/e): 497(MH⁺). 7.3.680N2-(4-Carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926584) The treatment ofN2-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith trifluoroacetic acid in THF:H₂O at room temperature affordedN2-(4-carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹HNMR (DMSO-d₆): δ10.01 (s, 1H), 8.64 (s, 1H), 7.45 (bd, 4H, J=7.2 Hz),6.90 (d, 2H, J=8.7 Hz), 6.75 (d, 2H, J=8.4 Hz), 4.80 (s, 2H), 4.38 (s,2H), 4.26 (q, 2H, J=7.2 Hz), 3.70 (s, 3H), 1.30 (t, 3H, J=7.2 Hz); LCMS:ret. time: 22.37 min.; purity: 100%; MS (m/e): 497 (MH⁺). 7.3.6815-Carboxy-N2-(3-hydroxyphenyl)-N4-[N-(L)-phenylglycine)-2-pyrimidineamine(R926535) The LiOH hydrolysis ofN2-(3-hydroxyphenyl)-5-ethoxycarbonyl-4-[N-(L)-phenyl glycine ethylester]-2-pyrimidineamine affored5-carboxy-N2-(3-hydroxyphenyl)-N4-[N-(L)-phenylglycine)-2-pyrimidineamine.¹H NMR (CD₃OD): δ8.89 (s, 1H), 8.50 (s, 1H), 7.43 (m, 2H), 7.33 (m, 3H),7.14 (m, 2H), 6.98 (m, 2H), 6.62 (m, 1H), 5.71 (s, 1H); LCMS: ret. time:17.75 min.; purity: 73%; MS (m/e): 382 (MH⁺). 7.3.6825-Amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925856) A suspension of6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-5-nitro-2,4-pyrimidinediamineand 10% Pd/C (10% by weight) in ethanol was prepared and reacted in aParr bottle under hydrogen gas (20 PSI) for 1 h. The reaction mixturewas filtered through Celite. Purification by column chromatography gave5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.30 (bs, 1H), 7.18-7.10 (m, 3H), 7.00 (t, 2H, J=8.1Hz), 6.59-6.54 (m, 1H), 6.33 (dd, 1H, J=2.1 and 11.1 Hz), 4.39 (q, 2H,J=6.9 Hz), 1.43 (t, 3H, J=6.9 Hz); LCMS: ret. time: 19.24 min.; purity:100 %; MS (m/e): 382 (MH⁺). 7.3.6835-Amino-6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine(R925857) In a manner similar to the preparation of5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine,6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine,hydrogen, and 10% Pd/C were reacted to yield5-amino-6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.16 (d, 1H, J=2.4 Hz), 7.07 (d, 1H, J=2.4 Hz), 7.04(dd, 1H, J=2.4 and 9.0 Hz), 6.84-6.79 (m, 2H), 6.70 (d, 1H, J=9.0), 4.43(q, 2H, J=7.8 Hz), 4.25 (s, 4H), 4.21 (bs, 4H), 1.43 (t, 3H, J=7.8 Hz);LCMS: ret. time: 23.70 min.; purity: 100 %; MS (m/e): 466 (MH⁺). 7.3.6845-Amino-N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine(R925865) In a manner similar to the preparation of5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine,6-ethoxycarbonyl-N2,N4-bis(ethoxycarbonylmethyl)-5-nitro-2,4-pyrimidinediamine,hydrogen, and 10% Pd/C were reacted to yield5-amino-N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ6.25 (bs, 2H), 4.38 (q, 2H, J=6.9 Hz), 4.23-4.14 (m,6H), 4.05 (bs, 2H), 1.39 (t, 3H, J=6.9 Hz), 1.30-1.22 (m, 6H); LCMS:ret. time: 17.67 min.; purity: 95 %; MS (m/e): 370 (MH⁺). 7.3.6855-Amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine(R926567) Hydrogenation ofN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamineusing Pd/C in MeOH at 40 PSI gave5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.47 (d, 2H, J=8.7 Hz), 7.41 (d, 2H, J=8.7 Hz), 6.88(d, 2H, J=8.1 Hz), 6.81 (d, 2H, J=8.7 Hz), 4.63 (s, 2H), 4.59 (s, 2H),4.41 (q, 2H, J=7.5 Hz), 4.29 (m, 4H), 1.44 (t, 3H), 1.31 (m, 6H); LCMS:ret. time: 26.15 min.; purity: 97%; MS (m/e): 554 (MH⁺). 7.3.686N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine(R926571) A dry reaction flask equipped with a rubber septum and a N₂inlet was charged with5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine,equimolar amount of pyridine and phenyl isocyanate at room temperature.The reaction was allowed to stirred at room temperature for overnightand the resulting reaction was poured over n-hexane to precipitate thedesired product,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.92 (s, 1H), 7.47 (s, 1H), 7.35 (bt, 5H, J=8.4 Hz),7.25 (bt, 2H, J=7.5 Hz), 7.03 (m, 2H), 6.81 (d, 2H, J=8.7 Hz), 6.76 (d,2H, J=8.7 Hz), 4.60 (s, 2H), 4.58 (s, 2H), 4.29 (m, 6H), 1.45 (m, 9H);LCMS: ret. time: 27.75 min.; purity: 91%; MS (m/e): 673 (MH⁺). 7.3.6875-Allylaminocarbonylamino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl)-2,4-pyrimidinediamine(R926585) In like manner to the preparation ofN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine,the reaction of5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith allyl isocyanate gave5-allylaminocarbonylamino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl)-2,4-pyrimidinediamine.LCMS: ret. time: 25.60 min.; purity: 91%; MS (m/e): 637 (MH⁺). 7.3.688N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylaminocarbonylamino)-2,4-5-pyrimidinetriamine(R926586) In like manner to the preparation ofN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine,the reaction of5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith ethoxycarbonyl isocyanate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylaminocarbonylamino)-2,4-pyrimidinediamine.LCMS: ret. time: 26.79 min.; purity: 88%; MS (m/e): 669 (MH⁺). 7.3.689N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylmethyleneaminocarbonylamino)-2,4-pyrimidinediamine (R926587) In like manner tothe preparation of N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine,the reaction of5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith ethylacetyl isocyanate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylmethyleneaminocarbonylamino)-2,4-pyrimidinediamine.LCMS: ret. time: 25.76 min.; purity: 96%; MS (m/e): 683 (MH⁺). 7.3.690N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(cyclopentylaminocarbonylamino)-2,4-pyrimidinediamine(R926588) In like manner to the preparation ofN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine,the reaction of5-amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith cyclopentyl isocyanate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(cyclopentylaminoacrbonylamino)-2,4-pyrimidinediamine.LCMS: ret. time: 27.36 min.; purity: 83%; MS (m/e): 665 (MH⁺). 7.3.691N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(chloroacetylaminocarbonylamino)-2,4-pyrimidinediamine(R926589) In like manner to the preparation ofN2,N4-bis(ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(N-phenylformyl-amino)-2,4-pyrimidinediamine,the reaction ofN5-amino-N2,N4-bis(ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediaminewith chloroacetylformyl isocyanate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(chloroacetylaminocarbonylamino)-2,4-pyrimidinediamine. LCMS: ret. time: 26.60 min.;purity: 100%; MS (m/e): 580 (MH⁺). 7.3.692 (R920669):N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-trifluoro-2,4-pyridinediamine Amixture of 2,4-dichloro-5-trifluoromethylpyrimidine (416 mg, 1.9 mmol),3,4-ethylenedioxyaniline (0.5 mL, 4.1 mmol), and concentrated HCl (0.1mL) in 1:9 acetone/H₂O (10 mL) was heated to reflux. After 1 h, thereaction was complete as determined by TLC. The mixture was cooled toroom temperature and EtOAc (30 mL) was added. The organic layer waswashed with 2 N HCl (2 × 15 mL), water (15 mL), and dried (Na₂SO₄). Theorganic layer was filtered through a silica gel pad, washing the filtercake with EtOAc, and concentrated. The material was purified bychromatography (silica gel, 95:5 dichloromethane/ethyl acetate) toaffordN2,N4-bis(3,4-ethylenedioxyphenyl)-5-trifluoro-2,4-pyridinediamine (380mg, 44%): Rf 0.27 (silica gel, 9.5:0.5 dichloromethane/ethyl acetate);mp 141-143° C.; ¹H NMR (300 MHz, CDCl₃) δ8.25 (s, 1H), 7.07 (m, 2H),6.99 (bs, 1H), 6.93-6.84 (m, 3H), 6.77-6.74 (m, 1H), 6.67 (bs, 1H),4.29-4.24 (m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ161.2, 157.9, 155.8, 143.7,132.6, 131.1, 117.5, 117.3, 114.4, 113.2, 110.3, 64.7, 64.5; IR (ATR)3446 cm⁻¹; ESI MS m/z 447 [C₂₁H₁₇F₃N₄O₄ + H]⁺; HPLC (Method C) >99%(AUC), t _(R) =8.5 min. Anal. Calcd for C₂₁H₁₇F₃N₄O₄: C, 56.50; H, 3.84;N, 12.55. Found: C, 56.46; H, 4.41; N, 12.57. 7.3.693 (R920668):N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-pyridyl)-2,4-pyrimidinediamineA mixture of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (280mg, 1 mmol), 3-aminopyridine (113 mg, 1.2 mmol), sodium t-butoxide (134mg, 1.4 mmol), binap (38 mg, 0.06 mmol), and palladium(II)acetate (14mg, 0.06 mmol) in 9 mL of toluene was purged with N₂ (3 cycles ofalternating N₂ and vacuum). The mixture was heated to 80° C. (oil-bathtemperature). After 24 h, the mixture was cooled to room temperature andEtOAc (30 mL) and of water (10 mL) was added. After stirring 15 min, theprecipitate was collected by filtration. A ¹H NMR spectrum and ESI massspectrum of the solid (150 mg) indicated the product (TLC analysis ofthe organic layer of the filtrate detected only starting materials). Thecrude product was slurried in 2 N HCl and the mixture was filtered. Thefiltrate was neutralized with 10% aqueous NaOH and concentrated. Thematerial was slurried with MeOH and the solids removed by filtration.The concentrated material was slurried in CH₃CN and TFA was added toafford a solution. N,Ndiisopropylethylamine was added to the solutionand the solid was collected by filtration, washing with CH₃CN followedby Et₂O to affordN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-pyridyl)-2,4-pyrimidinediamine(55 mg, 14%): Rf 0.42 (silica gel, 4:1:0.1:0.1 dichloromethane/ethylacetate/methanol/concentrated ammonium hydroxide); mp 251-253° C.; ¹HNMR (300 MHz, DMSO-d6) δ9.38 (s, 1H), 9.26 (s, 1H), 8.74 (s, 1H),8.20-8.17 (m, 1H), 8.09-8.08 (m, 2H), 7.29-7.28 (m, 1H), 7.23-7.17 (m,2H), 6.83-6.80 (m, 1H), 4.24 (m, 4H); ¹³C NMR (75 MHz, DMSO-d6) δ155.2,149.8, 142.9, 141.6, 140.5, 140.0, 139.8, 139.7, 137.5, 132.1, 124.8,123.0, 116.4, 115.1, 110.9, 64.1, 64.0; IR (ATR) 3264, 3195 cm⁻¹; APCIMS m/z 340 [C₁₇H₁₄FN₅O₂ + H]⁺. Anal. Calcd for C₁₇H₁₄FN₅O₂·0.5H₂O: C,58.70; H, 4.20; N, 20.13. Found: C, 58.71; H, 4.20; N, 19.51. 7.3.694(R920664):N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-n-hexyloxyphenyl)-2,4-pyrimidindiamineTo a magnetically stirred solution of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.25g, 0.89 mmol) in ethylene glycol (3.0 mL) under nitrogen at roomtemperature was added N,N-diisopropylethylamine (0.12 g, 0.89 mmol)followed by 4-hexyloxyaniline (0.27 g, 1.4 mmol). The reaction mixturewas heated to 170° C. for 5.5 h, cooled to room temperature andpartitioned between water (20 mL) and chloroform (20 mL). The aqueouslayer was extracted with chloroform (20 mL) and the combined organiclayers were dried (Na₂SO₄), filtered and concentrated in vacuo. Thecrude brown solid was purified by chromatography (silica gel, 2:1hexanes/ethyl acetate) to affordN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-n-hexyloxyphenyl)-2,4-pyrimidindiamine(0.09 g, 23%) as a white solid: Rf 0.53 (silica gel, 4:1chloroform/ethyl acetate); mp 115-117° C.; ¹H NMR (500 MHz, CDCl₃) δ7.90(d, J =3.2 Hz, 1H), 7.40 (d, J =8.9 Hz, 2H), 7.29 (d, J =2.5 Hz, 2H),6.98 (d, J =8.8 Hz, 1H), 6.88-6.82 (m, 3H), 6.61 (s, 1H), 4.29 (d, J=3.1 Hz, 4H), 3.94 (t, J =6.6, 6.7 Hz, 2H), 1.77 (m, 2H), 1.47 (m, 2H),1.35 (m, 4H), 0.92 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ156.3, 155.1,150.3, 143.6, 142.7, 140.3, 140,07 139.4, 133.0, 131.7, 121.9, 117.3,115.0, 114.7, 110.8, 68.6, 64.6, 31.8, 29.5, 25.9, 22.8, 14.2; IR (ATR)3357 cm⁻¹; ESI MS m/z 439 [C₂₄H₂₇FN₄O₃ + H]⁺; HPLC (Method B) 98.5%(AUC), t _(R) =7.9 min. Anal. Calcd for C₂₄H₂₇FN₄O₃: C, 65.74; H, 6.21;N, 12.78. Found: C, 65.34; H, 6.19; N, 12.96. 7.3.695 (R920666):N2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamineTo a magnetically stirred solution of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.25g, 0.89 mmol) in ethylene glycol (3.0 mL) under nitrogen at roomtemperature was added N,N-diisopropylethylamine (0.12 g, 0.89 mmol)followed by 4-butoxyaniline (0.18 g, 1.1 mmol). The reaction mixture washeated to 185° C. for 5 h, cooled to room temperature, and partitionedbetween water (20 mL) and ethyl acetate (20 mL). The aqueous layer wasextracted with ethyl acetate (20 mL) and the combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo. The crude brownsolid was purified by chromatography (silica gel, 2:1 hexanes/ethylacetate) to affordN2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine(0.18 g, 49%) as a tan solid: Rf 0.66 (silica gel, 4:1 chloroform/ethylacetate); mp 133-135° C.; ¹H NMR (300 MHz, CDCl₃) δ7.89 (d, J =3.2 Hz,1H), 7.39 (d, J =8.9 Hz, 2H), 7.28 (d, J =2.5 Hz, 1H), 6.95 (dd, J =8.7,2.5 Hz, 1H) 6.90-6.81 (m, 4H), 6.60 (d, J =2.4 Hz, 1H), 4.27 (s, 4H),3.94 (t, J =6.5 Hz, 2H), 1.80-1.71 (m, 2H), 1.55-1.42 (m, 2H), 0.97 (t,J =7.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ156.3, 155.1, 150.4, 143.6,142.7, 140.3, 140.0, 139.4, 133.0, 131.7, 121.9, 117.3, 115.0, 114.7,110.8, 68.2, 64.7, 64.5, 31.6, 19.4, 14.0; IR (ATR) 3356 cm⁻¹; ESI MSm/z 411 [C₂₂H₂₃FN₄O₃ + H]⁺; HPLC (Method A) >99% (AUC), t _(R) =17.3min. Anal. Calcd for C₂₂H₂₃FN₄O₃: C, 64.38; H, 5.65; N, 13.65. Found: C,62.64; H, 5.59; N, 13.15. 7.3.696 (R920670):N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineTo a solution of2-chloro-N4-(4-ethyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.93mmol) in ethylene glycol (3 mL) under nitrogen at room temperature wasadded i-Pr₂EtN, 0.93 mmol) followed by 3,4-ethylenedioxyaniline (0.17 g,1.12 mmol). The reaction mixture was heated to 200° C. for 5 h and thencooled to room temperature. The mixture was partitioned between H₂O (20mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (20mL). The combined organic layers were dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude brown solid was purified bychromatography (2:1 CHCl₃/EtOAc) to affordN4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(0.21 g, 60%) as a tan solid: Rf 0.42 (4:1 CHCl₃/EtOAc); mp 163.8-167.2°C. (DSC); ¹H NMR (300 MHz, CDCl₃) δ7.89 (d, J =2.8 Hz, 1H), 7.50-7.45(m, 2H), 7.17 (d, J =2.5 Hz, 1H), 6.92-6.86 (m, 3H), 6.80-6.75 (m, 2H),6.64 (bs, 1H), 4.26-4.21 (m, 4H), 4.03 (q, J =7.0, 2H), 1.42 (t, J =6.9Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ156.1,150.6, 143.6, 142.8, 140.3,140.0, 139.5, 139.3, 134.0, 130.8, 123.2, 117.2, 115.1, 113.6, 109.4,64.6, 64.0, 15.1; IR (ATR) 3403 cm⁻¹; ESI MS m/z 383 [C₂₀H₁₉FN₄O₃ + H]⁺;HPLC (Method A) 98.1% (AUC), t _(R) =12.0 min. Anal. Calcd forC₂₀H₁₉FN₄O₃: C, 62.82; H, 5.01; N, 14.65. Found: C, 62.06; H, 5.01; N,14.35. 7.3.697 (R920671):N4-(4-n-Butyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamineIn like manner to the preparartionofN4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine with3,4-ethylenedioxyanilinegaveN4-(4-n-butyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine.The crude product was purified by chromatography (2:1 CHCl₃/EtOAc) ;(0.17 g, 52%) as a tan solid: Rf 0.51 (4:1 CHCl₃/EtOAc); mp 149.6-151.4°C. (DSC); ¹H NMR (300 MHz, CDCl₃) δ7.88 (d, J =3.4 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.18 (d, J =2.4 Hz, 1H), 6.91-6.86 (m, 3H), 6.78-6.75 (m,2H), 6.62 (bs, 1H), 4.26-4.22 (m, 4H), 3.96 (t, J =6.5, 2H), 1.82-1.73(m, 2H), 1.56-1.44 (m, 2H), 0.98 (t, J =7.4 Hz, 3H); ¹³C NMR (75 MHz,CDCl₃) δ156.1,150.8, 143.6, 142.8, 140.2, 139.9, 139.5, 139.2, 133.9,130.7, 123.1, 117.1, 115.0, 113.5, 109.4, 68.2, 64.6, 31.6, 19.4, 14.0;IR (ATR) 3365 cm⁻¹; ESI MS m/z 411 [C₂₂H₂₃FN₄O₃ + H]⁺; HPLC (Method A)99.0% (AUC), t _(R) =13.2 min. Anal. Calcd for C₂₂H₂₃FN₄O₃: C, 64.38; H,5.65; N, 13.65. Found: C, 63.63; H, 5.60; N, 13.38. 7.3.698 (R920672):N4-(4-n-Hexyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamineIn like manner to the preparartionofN4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(4-n-hexyloxyphenyl)-5-fluoro-4-pyrimidineamine with3,4-ethylenedioxyaniline gaveN4-(4-n-hexyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine.The crude product was purified by chromatography (2:1 CHCl₃/EtOAc) (0.22g, 69%) as a tan solid: Rf 0.54 (4:1 CHCl₃/EtOAc); mp 124.0-125.2° C.(DSC); ¹H NMR (300 MHz, CDCl₃) δ7.88 (d, J =3.2 Hz, 1H), 7.47 (d, J =8.9Hz, 2H), 7.18 (d, J =2.4 Hz, 1H), 6.91-6.86 (m, 3H), 6.78-6.74 (m, 2H),6.62 (d, J =1.8 Hz, 1H), 4.26-4.22 (m, 4H), 3.96 (t, J =6.5, 2H),1.83-1.74 (m, 2H), 1.51-1.42 (m, 2H), 1.36-1.32 (m, 4H), 0.93-0.89 (t, J=6.7 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ156.1, 150.5, 143.5, 143.0,142.8, 140.2, 139.9, 139.5, 139.2, 133.9, 130.7, 123.1, 117.1, 115.0,113.5, 109.3, 68.5, 64.7, 64.5, 31.8, 29.5, 25.9, 22.8, 14.2; IR (ATR)3378 cm⁻¹; ESI MS m/z 439 [C₂₄H₂₇FN₄O₃ + H]⁺; HPLC (Method A) >99%(AUC), t _(R) =14.6 min. Anal. Calcd for C₂₄H₂₇FN₄O₃: C, 65.74; H, 6.21;N, 12.78. Found: C, 65.52; H, 6.23; N, 12.66. 7.3.699 (R920818):5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineTo a mixture of 4-amino-[(1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene(1.2 g, 6.2 mmol), 1-propanol (40 mL) and trifluoroacetic acid (1 mL)was added 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyridineamine (1.5 g,6.2 mmol). The mixture was heated at 110° C. for 17 h and then cooled toroom temperature. The purple solid that formed was collected byfiltration, washing with 1-propanol (30 mL) to afford5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(1.6 g, 65%) as an off-white solid: Rf 0.55 (6:3:1 CHCl₃/CH₃OH/NH₄OH);mp (DSC) 191.2-193.7° C., 257.2-260.0° C., 344.7-345.2° C.; ¹H NMR (300MHz, DMSO-d ₆) δ9.39 (s, 1H), 9.21 (s, 1H), 9.10 (s, 1H), 8.04 (d, J=3.8 Hz, 1H), 7.59 (d, J =9.1 Hz, 2H), 7.38 (s, 1H), 7.23 (t,J =8.1 Hz,1H), 7.17 (d, J =1.8 Hz, 1H), 7.05 (t, J =8.1 Hz, 1H), 6.93 (d, J =9.1Hz, 2H), 6.50 (dd, J =1.8, 8.1 Hz, 1H), 5.40 (s, 2H); ¹³C NMR (75 MHz,DMSO-d ₆) δ157.3, 155.3, 153.5, 151.9, 149.8, 149.7, 141.0 (d,JC-F=150.0 Hz), 139.7, 138.7, 135.0, 128.9, 120.2, 114.8, 110.3, 108.7,59.6; IR (ATR) 3338, 2923, 2581, 1724, 1661, 1580, 1557 cm⁻¹; ESI MS m/z395 [C₁₈H₁₅FN₈O₂ + H]⁺; HPLC (Method A) 96.5% (AUC), t _(R) =6.9 min.7.3.700 (R920819):N4-(3-Hydroxyphenyl)-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineTo a mixture of 4-amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene(0.1 g, 0.5 mmol), 1-propanol (2 mL) and trifluoroacetic acid (0.2 mL)was added 2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (0.1 g, 0.5mmol). The mixture was heated at 110° C. for 17 h and then cooled toroom temperature. The purple solid that formed was collected byfiltration, washing with 1-propanol (5 mL) to affordN4-(3-hydroxyphenyl)-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(59.4 mg, 30%) as an off-white solid: Rf 0.51 (6:3:1 CHCl₃/CH₃OH/NH₄OH);mp 292-295° C. dec; ¹H NMR (300 MHz, DMSO-d ₆) δ9.34 (s, 2H), 9.13 (s,1H), 7.95 (d, J =5.8 Hz, 1H), 7.64 (d, J =8.9 Hz, 2H), 7.39 (s, 1H),7.19 (t,J =8.1 Hz, 1H), 7.05 (t, J =8.1 Hz, 1H), 6.96 (d, J =8.9 Hz,2H), 6.43 (dd, J =1.4, 8.1 Hz, 1H), 6.20 (d, J =5.8 Hz, 1H), 5.40 (s,2H); ¹³C NMR (75 MHz, DMSO-d ₆) δ160.4, 158.5, 157.5, 154.0, 153.7,152.2, 140.6, 134.4, 129.1, 120.9, 114.7, 111.0, 109.5, 107.2, 98.4,59.6; IR (ATR) 3321, 2920, 2581, 1649, 1605, 1487 cm⁻¹; ESI MS m/z 377[C₁₈H₁₆N₈O₂ + H]⁺; HPLC (Method A) 97.6% (AUC), t _(R) =7.6 min. 7.3.701(R920820): N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine To amixture of 4-amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene (0.2 g,0.9 mmol), 1-propanol (4 mL) and trifluoroacetic acid (0.2 mL) was added2-chloro-N4-(3-hydroxyphenyl)-5-methyl-4-pyrimidineamine (0.2 g, 0.9mmol). The mixture was heated at 110° C. for 17 h and then cooled toroom temperature. The purple solid that formed was collected byfiltration, washing with 1-propanol (10 mL) to affordN4-(3-hydroxyphenyl)-5-methyl-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(0.3 g, 89%) as an off-white solid: Rf 0.44 (6:3:1 CHCl₃/CH₃OH/NH₄OH);mp (DSC) 255.3-262.4° C.; ¹H NMR (300 MHz, DMSO-d ₆) δ10.32 (s, 1H),9.65 (s, 2H), 7.85 (s, 1H), 7.38 (d, J =10.5 Hz, 2H), 7.17 (s, 1H), 7.12(t,J =7.9 Hz, 1H), 7.06 (s, 1H), 6.90 (d, J =10.5 Hz, 2H), 6.68 (d, J=7.9 Hz, 1H), 5.45 (s, 2H), 2.14 (s, 3H); ¹³C NMR (75 MHz, DMSO-d ₆)δ161.6, 157.9, 154.5, 153.7, 151.2, 140.4, 138.2, 130.1, 129.4, 123.3,115.9, 115.4, 113.5, 112.4, 107.5, 59.8, 13.7; IR (ATR) 3214, 3051,2157, 1632, 1596, 1547 cm⁻¹; ESI MS m/z 391 [C₁₉H₁₈N₈O₂ + H]⁺; HPLC(Method A) >99% (AUC), t _(R) =7.9 min. 7.3.702N4-(3-Benzyloxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine[NEED R NO.] A mixture ofN4-(3-benzyloxyphenyl)-2-chloro-4-pyrimidineamine (0.25 g, 0.82 mmol),4-amino-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.17 g,0.82 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (10 mL) washeated to 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol, the crude product was preadsorbed onto silica gelusing 95:5 methylene chloride /methanol and purified by flashchromatography (95:5 methylene chloride /methanol) to giveN4-(3-benzyloxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a tan solid (0.20 g, 52%): ¹H NMR (300 MHz, DMSO-d6) δ8.00 (br s,1H), 7.86 (d, J =6.1 Hz, 1H), 7.53-7.20 (m, 13H), 7.14 (d, J =9.0 Hz,2H), 6.93 (d, J =6.1 Hz, 1H), 6.13 (d, J =6.1 Hz, 1H), 5.27 (s, 2H),4.04 (s, 3H); ESI MS m/z 481 [C₂₆H₂₄N₈O₂ + H]⁺ 7.3.703 (R920917):N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineA mixture ofN4-(3-benzyloxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine(0.20 g, 0.42 mmol) and 5% Pd/C (0.10 g) in 14:1 ethanol/concentratedhydrochloric acid (40 mL) was at room temperature was shaken in ahydrogen atmosphere at 50 psi. After 3 h no further hydrogen uptake wasobserved. The reaction mixture was filtered through diatomaceous earth,the solids washed with 95:5 methylene chloride/methanol and the filtrateconcentrated to affordN4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine(0.16 g, 95%) as a tan solid: Rf 0.23 (95:5 methylenechloride/methanol); mp (DSC) 207.1-212.8, 287.4-295.7° C.; ¹H NMR (300MHz, DMSO-d6) δ10.87 (br s, 1H), 10.81 (br s, 1H), 9.62 (br s, 1H),8.08-8.06 (m, 1H), 7.72 (d, J =9.0 Hz, 2H), 7.24 (br s, 1H), 7.20-7.00(m, 3H), 6.61 (m, 2H), 6.46, (d, J =6.0 Hz, 1H), 5.38 (s, 2H), 4.40 (s,3H); ¹³C NMR (75 MHz, DMSO-d6) δ161.3, 160.1, 157.0, 154.3, 151.6,141.7, 137.6, 129.1, 128.6, 123.4, 114.4, 111.9, 111.5, 108.3, 98.6,59.6, 38.0; IR (ATR) 2975, 1639, 1602, 1521cm⁻¹; ESI MS m/z 391[C₁₉H₁₈N₈O₂ + H]⁺; HPLC (Method A) 94.9 % (AUC), t _(R) =8.19 min.7.3.704N4-(3-Benzyloxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine[NEED R NO.] A mixture ofN4-(3-benzyloxyphenyl)-2-chloro-4-pyrimidineamine (0.52 g, 1.69 mmol),4-amino-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene (0.34 g,1.69 mmol) and trifluoroacetic acid (0.4 mL) in 1-propanol (10 mL) washeated to 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol. The crude product was preadsorbed onto silica gelusing 95:5 methylene chloride /methanol and purified by flashchromatography (95:5 methylene chloride /methanol) affording therequisite productN4-(3-benzyloxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl)-2,4-pyrimidineamineas a tan solid (0.41 g, 51%): ¹H NMR (300 MHz, DMSO-d6) δ7.85 (d, J =6.1Hz, 1H), 7.49-7.04 (m, 14H), 6.93 (d, J =9.0 Hz, 2H), 6.60-6.72 (m, 1H),6.11 (d, J =6.1 Hz, 1H), 5.14 (s, 2H), 4.34 (s, 3H); ESI MS m/z 481[C₂₆H₂₄N₈O₂ + H]⁺ 7.3.705 (R920910):N4-(3-Hydroxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineA mixture ofN4-(3-benzyloxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine(0.40 g, 0.42 mmol) and 5% Pd/C (0.10 g) in 14:1 ethanol/concentratedhydrochloric acid (40 mL) at room temperature was shaken in anatmosphere of hydrogen at 50 psi. After 3 h no further hydrogen uptakewas observed. The reaction mixture was filtered through diatomaceousearth, the solids washed with 95:5 methylene chloride/methanol and thefiltrate concentrated to affordN4-(3-hydroxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine(0.29 mg, 89%) as a beige solid: Rf 0.43 (95:5 methylenechloride/methanol); mp 140-152° C.; ¹H NMR (300 MHz, DMSO-d6) δ10.24 (brs, 1H), 9.98 (br s, 1H), 9.52 (br s, 1H), 7.94 (d, J =6.6 Hz, 2H), 7.54(d, J =8.8 Hz, 2H), 7.43 (s, 1H), 7.26 (s, 1H), 7.18-7.01 (m, 3H), 6.53,(d, J =7.5 Hz, 1H), 6.37, (d, J =6.6 Hz, 1H), 5.52 (s, 2H), 4.13 (s,3H); ¹³C NMR (75 MHz, DMSO-d6) δ160.2, 157.2, 154.5, 153.0, 151.2,146.8, 139.9, 131.8, 128.7, 122.3, 114.7, 111.4, 110.5, 107.5, 99.5,59.5, 33.3; IR (ATR) 3042, 1578, 1504, 1459 cm⁻¹; ESI MS m/z 391[C₁₉H₁₈N₈O₂ + H]⁺; HPLC (Method A) 95.8 % (AUC), t _(R) =8.82 min.7.3.706 (R920861):5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineA mixture of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(0.22 g, 0.93 mmol,4-amino-[(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.19 g,0.93 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (8 mL) washeated to 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol. The crude product was preadsorbed onto silica gelusing 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride /methanol) affording therequisite product5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a purple solid (0.18 g, 49%): Rf 0.47 (95:5 methylenechloride/methanol); mp 219-224° C.; ¹H NMR (300 MHz, DMSO-d6) δ9.36 (s,1H), 9.18 (s, 1H), 9.06 (s, 1H), 8.05 (d, J =6.0 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.27 (d, J =9.0 Hz, 1H), 7.09 (t, J =8.0 Hz, 2H), 6.94 (d,J =9.0 Hz, 2H), 6.49 (dd, J =8.0, 2.1 Hz, 1H),, 5.45 (s, 2H), 4.11 (s,3H); ¹³C NMR (75 MHz, DMSO-d6) δ157.4, 155.5, 151.7, 151.6, 149.6,149.5, 142.0, 142.0, 139.3 (d, JC-F =127.5 Hz), 135.3, 128.9, 120.1,114.9, 112.3, 110.3, 108.5, 58.5, 33.9; IR (ATR) 3278, 1586, 1542, 1508cm⁻¹; ESI MS m/z 409 [C₁₉H₁₇FN₈O₂+H]⁺; HPLC (Method A) 98.2 % (AUC), t_(R) =7.69 min. Anal. Calcd for C₁₉H₁₇FN₈O₂·0.5H₂O: C, 54.74; H, 4.23;N, 26.88. Found: C, 54.55; H, 4.02; N, 26.62. 7.3.707 (R920860):5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineA mixture of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine(0.31 g, 1.28 mmol),4-amino-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.26 g,1.28 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (8 mL) washeated at 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol. The crude product was preadsorbed onto silica gelusing 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride /methanol) to give5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a purple solid (0.20 g, 37 %): Rf 0.63 (95:5 methylenechloride/methanol); mp 220-224° C.; ¹H NMR (300 MHz, DMSO-d6) δ9.36 (s,1H), 9.17 (s, 1H), 9.02 (s, 1H), 8.05 (d, J =2.8 Hz, 1H), 7.57 (d, J=9.1 Hz, 2H), 7.27 (d, J =8.0 Hz, 1H), 7.10 (dt, J =2.8, 8.0 Hz, 2H),6.91 (d, J =9.1 Hz, 2H), 6.49 (dd, J =8.0, 2.8 Hz, 1H), 5.29 (s, 2H),4.39 (s, 3H); ¹³C NMR (75 MHz, DMSO-d6) δ162.2, 157.4, 155.5, 152.1,149.6, 149.5, 140.9 (d, JC-F =142.0 Hz), 140.5, 140.2, 138.7, 134.8,128.9, 120.2, 114.5, 112.2, 110.2, 108.5, 60.5, 38.5; IR (ATR) 3274,1587, 1507 cm⁻¹; ESI MS m/z 409 [C₁₉H₁₇FN₈O₂ + H]⁺; HPLC (Method A) 97.2% (AUC), t _(R) =8.04 min. Anal. Calcd for C₁₉H₁₇FN₈O_(2.): C, 55.88; H,4.20; N, 27.44. Found: C, 55.56; H, 4.10; N, 27.17. 7.3.708 (R920894):N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineA mixture of 2-chloro-N4-(3-hydroxyphenyl)-5-methyl-4-pyrimidineamine(0.20 g, 0.85 mmol,4-amino-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.17 g,0.85 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (8 mL) washeated at 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol. The crude product was preadsorbed onto silica gelusing 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride /methanol) to giveN4-(3-hydroxyphenyl)-5-methyl-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a purple solid (0.18 g, 52%): Rf 0.61 (95:5 methylenechloride/methanol); mp 209-211° C.; ¹H NMR (300 MHz, DMSO-d6) δ9.30 (s,1H), 8.82 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.60 (d, J =9.0 Hz, 2H),7.18-7.05 (m, 3H), 6.89 (d, J =9.0 Hz, 2H), 6.48 (t, J =7.1 Hz, 1H),5.27 (s, 2H), 4.39 (s, 3H), 2.08 (s, 3H); ¹³C NMR (75 MHz, DMSO-d6)δ161.7, 158.6, 157.5, 156.7, 154.7, 151.2, 140.2, 134.6, 134.6, 128.1,119.3, 114.0, 112.6, 109.4, 108.9, 104.7, 59.8, 38.0, 12.9; IR (ATR)3003, 1602, 1581, 1531, 1507 cm⁻¹; ESI MS m/z 405 [C₂₀H₂₀N₈O₂ + H]⁺;HPLC (Method A) 96.8 % (AUC), t _(R) =8.23 min. 7.3.709 (R920893):N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineA mixture of 2-chloro-N4-(3-hydroxyphenyl)-5-methyl-4-pyrimidineamine(0.20 g, 0.85 mmol),4-amino-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (0.17 g,0.85 mmol) and trifluoroacetic acid (0.2 mL) in 1-propanol (8 mL) washeated at 110° C. for 24 h. The reaction was concentrated to remove mostof the 1-propanol. The crude product was preadsorbed onto silica gelusing 95:5 methylene chloride/methanol and purified by flashchromatography (95:5 methylene chloride /methanol) to giveN4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamineas a purple solid (0.14 g, 42%): Rf 0.44 (95:5 methylenechloride/methanol); mp 219-221° C.; ¹H NMR (300 MHz, DMSO-d6) δ9.32 (s,1H), 8.85 (s, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.64 (d, J =9.0 Hz, 2H),7.20-7.07 (m, 3H), 6.91 (d, J =9.0 Hz, 2H), 6.50 (dd, J =8.0, 1.2 Hz,1H), 5.45 (s, 2H), 4.12 (s, 3H), 2.09 (s, 3H); ¹³C NMR (75 MHz, DMSO-d6)δ158.0, 157.0, 156.1, 154.3, 150.6, 150.0, 139.6, 134.6, 127.5, 118.6,113.7, 112.0, 108.8, 108.2, 104.2, 57.4, 32.7, 12.3; IR (ATR) 3428,1595, 1567, 1509 cm⁻¹; ESI MS m/z 405 [C₂₀H₂₀N₈O₂ + H]⁺; HPLC (Method A)98.5 % (AUC), t _(R) =7.89 min. Anal. Calcd for C₂₀H₂₀N₈O₂. H₂O: C,57.00; H, 5.02; N, 26.59. Found: C, 56.86; H, 4.92; N, 26.50. 7.3.710N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-(1,2,3,4-tetrazol-5-yl)-2,4-pyrimidinediamine(R925810) In a manner similar to experiment #,N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamineand sodium azide were reacted to yieldN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-(1,2,3,4-tetrazol-5-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 25.8 min.; purity: 95%; MS: 535 (MH⁺). 7.3.711N2-[4-(N-Cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R925838) In like manner tothe preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediaminewith cyclopropylmethylamine gaveN2-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: MS(m/e): 478 (MH⁺). 7.3.7125-Ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925839) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediaminewith methylamine hydrochloride gave5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.LCMS: MS (m/e): 438 (MH⁺). 7.3.713 N2-[4-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R925840) In like manner to thepreparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediaminewith 3-amino-1,2-propanediol gaveN2-[4-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: MS (m/e): 498 (MH⁺). 7.3.714 N2,N4-Bis[4-[N-(3-methoxybenzylamino)carbonylmethyleneoxy]phenyl]-5-bromo-2,4-pyrimidinediamine (R925841) Inlike manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2,N4-bis[4-ethoxycarbonylmethyleneoxyphenyl)-5-bromo-2,4-pyrimidinediaminewith 3-methoxybenzylamine gave N2,N4-bis[4-[N-(3-methoxybenzylamino)carbonylmethyleneoxy]phenyl]-5-bromo-2,4-pyrimidinediamine. LCMS: ret.time: 25.94 min.; purity: 95 %; MS (m/e): 727 (MH⁺). 7.3.7155-Bromo-N4-[4-[(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R925842) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-bromo-N4-(4-ethoxycarbonylmethyleneoxyphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith cyclopropylmethylamine gave5-bromo-N4-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 20.63 min.; purity: 100 %; MS (m/e): 485 (MH⁺). 7.3.7165-Bromo-N2-(3-hydroxyphenyl)-N4-[4-(N-3-methoxybenzylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R925843) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-bromo-N4-(4-ethoxycarbonylmethyleneoxyphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediaminewith 3-methoxybenzylamine gave5-bromo-N2-(3-hydroxyphenyl)-N2-(3-hydroxyphenyl)-N4-[4-(N-3-methoxybenzylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 22.34 min.; purity: 90 %; MS (m/e): 551 (MH⁺). 7.3.717N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine(R926698) In a manner similar to the preparation ofN4-(4-tert-butylphenyl)-5-fluoro-N2-(2,3-dihydro-2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamineand LiOH were reacted to yieldN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine.7.3.718N2,N4-Bis(4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926016) In a manner similar to the preparation ofN2-N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethylaniline gaveN2,N4-bis(4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ8.06 (bs, 1H), 7.75 (d, 2H, J=9 Hz), 7.67 (d, 2H, J=9Hz),7.63 (d, 2H, J=9Hz), 7.54 (d, 2H, J=9 Hz), 7.19 (bs, 1H), 6.96 (s, 1H);¹⁹F NMR (CDCl₃): δ-17598 (s, 3F), -17676 (s, 3F), -46549 (s, 1F); HPLC:85% pure. 7.3.719N2-(3,4-Ethylenedioxyphenyl)-N4-(3,4-methylenedioxyphenylhydrazinyl)-5-fluoro-2-pyrimidineamine(R926406) In a manner similar to the preparation ofN2-(3-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoroN4-(3,4-methylenedioxyphenylhydrazinyl)-4-pyrimidineamine with3,4-ethylenedioxyaniline gaveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3,4-methylenedioxyphenylhydrazinyl)-2-pyrimidineamine.¹HNMR (CD₃OD): δ7.82 (d, 1H, J=3.6 Hz), 7.52 (dd, 1H, J=1.8 and 7.5 Hz),7.40 (d, 1H, J=1.2 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.92 (d, 1H, J=8.4 Hz),6.85 (dd, 1H, J=2.1 and 8.7 Hz), 6.45 (d, 1H, J=9Hz), 6.06 (s, 2H), 4.10(s, 4H); LCMS: ret. time: 12.14 min.; purity: 88%; MS (m/e): 426 (MH⁺).7.3.720N2,N4-Bis(4-ethoxycarbonylmethylenedioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R926566) To a solution of 2,4-dichloro-5-nitropyrimidine (0.264 g, 1mmol) in EtOAc (10 mL) at 0° C. was added diisopropylethyl amine (0.200mL) followed by ethyl 4-aminophenoxy acetate (0.585 g, 3 mmol) and thenshaken at room temperature for 2 h. The reaction was quenched with waterand extracted with EtOAc. The EtOAc extract was washed with 2N HCl andwater. The solvent was evaporated and the residue was purified bycrystallization using EtOAc/hexanes to affordN2,N4-bis(4-ethoxycarbonylmethylenedioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine(R926566). ¹H NMR (CDCl₃): 10.32 (s, 1H), 7.42 (s, 1H), 7.40 (d, 2H,J=8.7 Hz), 7.32 (d, 2H, J=8.7 Hz), 6.93 (d, 2H, J=8.7 Hz), 6.82 (d, 2H,J=8.7 Hz), 4.67 (s, 2H), 4.62 (s, 2H), 4.47 (q, 2H, J=7.5 Hz), 4.30 (m,4H), 1.42 (t, 3H, J=6.9 Hz), 1.31 (m, 6H); LCMS: ret. time: 32.10 min.;purity: 100%; MS (m/e): 584 (MH⁺). 7.3.721N2,N4-Bis[2-(methylthio)-1,3-benzothiaz-6-yl]-5-fluoro-2,4-pyrimidinediamine(R950202) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine and2-(methylthio)-1,3-benzothiazol-6-amine were reacted to prepareN2,N4-bis[2-(methylthio)-1,3-benzothiaz-6-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 24.98 min.; purity: 84.6%; MS (m/e): 486.80 (MH⁺).7.3.722N4-[3-(2-Hydroxyethyleamino)phenyl]-N2-[3-(N-(N-methyl)-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950240) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamineand N-methylpiperazine were reacted to giveN4-[3-(2-hydroxyethylenoxy)phenyl]-N2-[3-(N-(N-methyl)-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.36 min.; purity: 97.6%; MS (m/e): 495.42 (MH⁺).7.3.723N4-[3-(2-Hydroxyethyleamino)phenyl]-N2-[3-(N-piperazino)-carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine(R950241) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethyleneamino)phenyl]-2,4-pyrimidinediamineand piperazine were reacted to giveN4-[3-(2-hydroxyethyleneamino)phenyl]-N2-[3-(N-piperazino)-carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 13.21 min.; purity: 100%; MS (m/e): 481.40 (MH⁺).7.3.724(±)-N4-(3-Aminophenyl)-5-fluoro-N2-(3-(3-carboxy-3-D,L-N-phtaloylamino)propylenecarbonylaminophenyl)-2,4-pyrimidinediamine(R950251) N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine andN-phtaloyl-DL-glutamic anhydride were reacted in DMF to giveN4-(3-aminophenyl)-5-fluoro-N2-(3-(3-carboxy-3-D,L-N-phtaloylamino)propylenecarbonylaminophenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 19.41 min.; purity: 95.7%; MS (m/e): 569.98 (MH⁺).7.3.725(±)-N4-(3-Aminophenyl)-5-fluoro-N2-[3-(3-carboxy-3-amino)propylenecarbonylaminophenyl]-2,4-pyrimidinediamine(R950255)(±)-N4-(3-Aminophenyl)-5-fluoro-N2-[3-(3-carboxy-3-D,L-N-phtaloylamino)propylenecarbonylaminophenyl]-2,4-pyrimidinediaminewas reacted with hydrazine to giveN4-(3-aminophenyl)-5-fluoro-N2-[3-(3-carboxy-3-amino)propylenecarbonylaminophenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 11.98 min.; purity: 90.1%; MS (m/e): 440.3 (MH⁺).7.3.726 5-Methoxycarbonyl-N2,N4-bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (R926559) In likemanner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-ethoxycarbonyl-N2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith pyrrolidine gave 5-methoxycarbonyl-N2,N4-bis[4-(N-pyrrolidino)methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine. The ethylester at 5-position was exchanged to methyl ester in methanol as asolvent. MS (m/e): 575 (MH⁺). 7.3.727N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyridinediamine(R925565) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine with ethyl 4-aminophenoxyacetate gaveN2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyridinediamine.MS (m/e): 485 (MH⁺). 7.3.728N2-(3-Ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(3,4-tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine(R926799) In a manner similar to the preparation ofN2-(3-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction of ethyl 3-aminophenoxyacetate with2-chloro-5-ethoxycarbonyl-N4-(3,4-tetrafluoroethylenedioxyphenyl)-4-pyrimidineaminegaveN2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(3,4-tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine.MS (m/e): 567 (MH⁺). 7.3.729N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-2-(D)-(+)-biotinylethylamino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926811) To a solution of D-(+)-biotin andN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DMF at -20° C. was added diisopropylethylamine and the mixture wasshaken for 10 minutes. To this mixture was addedbenzotriazole-1-yl-oxy-tris(dimethylamino)-phosphoniumhexafluorophosphate(BOP) and shaken at room temperature for 24 h. The reaction was quenchedwith water and extracted with ethyl acetate. The ethyl acetate extractwas washed with aqueous solution of NaHCO3 and finally with water. Theresidue obtained after the removal of solvent was purified bypreparative TLC to obtain the desiredN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-2-(D)-(+)-biotinylethylamino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine. LCMS: ret. time:19.29 min.; purity: 99%; MS (m/e): 682 (M⁺). 7.3.7305-Fluoro-N4-(3-hydroxyphenyl)-N2[2-(N-methyl-N-2-hydroxyethyl)carbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R926725)In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of5-fluoro-N4-(3-hydroxyphenyl)-N2[2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediaminewith 2-(N-methyl)ethanolamine gave5-fluoro-N4-(3-hydroxyphenyl)-N2[2-(N-methyl-N-2-hydroxyethyl)carbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.LCMS: ret. time: 14.87 min.; purity: 98%; MS: 438 (MH⁺). 7.3.731N2,N4-Bis(3-ethoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926228) In like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reactionof 2,4-dichloro-5-fluoropyrimidine and 3-ethoxycarbonylaniline gaveN2,N4-bis(3-ethoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS:ret. time: 26.55 min.; purity: 100%; MS (m/e): 425 (MH⁺). 7.3.732N2-(3-chloro-4-methylbenzyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R908696) In a manner similar to the preparation ofN2-(3-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction of2-chloro-N4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-chloro-4-methylbenzylamine gaveN2-(3-chloro-4-methylbenzyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 25.38 min.; purity: 99 %; MS (m/e): 401 (MH⁺). 7.3.733(±)-N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-phenylethyl)-2,4-pyrimidinediamine(R908697) In a manner similar to the preparation ofN2-(3-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineamine,the reaction of2-chloro-N4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with(±)-2-aminoethylbenzene gave(±)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-phenylethyl)-2,4-pyrimidinediamine.LCMS: ret. time: 23.48 min.; purity: 99 %; MS (m/e): 367 (MH⁺). 7.3.734N2-(3-Ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R925745) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-ethoxycarbonylaniline gaveN2-(3-ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.04 (bs, 1H), 7.94 (bs, 1H), 7.90 (bd, 1H), 7.68 (bd,1H, J=7.5 Hz), 7.35 (t, 1H, J=8.1 Hz), 7.28 (d, 1H, J=2.4 Hz), 7.07 (s,1H), 6.93 (dd, 1H, J=3 and 8.7 Hz), 6.83 (d, 1H, J=9 Hz), 6.64 (bs, 1H),4.36 (q, 2H, J=7.2 Hz), 4.26 9s, 4H), 1.35 (t, 3H, J=7.5 Hz); ¹⁹F NMR(CDCl₃): - 47247; LCMS: ret. time: 15.88.; purity: 100%; MS (m/e): 411(MH⁺). 7.3.735 N4-(3,4-Difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920394) A solutionof N-methyl 3-aminophenoxyacetamide (1 equivalent) and2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine (1.2equivalents) in MeOH was shaken in a sealed tube at 100° C. for 24 hoursfor 24 h. Upon cooling to the room temperature, it was diluted withethyl acetate. The resulting solid was filtered and washed with amixture of ethyl acetate: n-hexanes (1:1; v/v) to obtainN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.05 (bs, 1H), 9.83 (bs, 1H), 8.23 (d, 1H, J=2.7Hz), 7.98 (m, 2H), 7.52 (m, 1H), 7.39 9m, 1H), 7.20 (m, 3H), 6.60 (m,1H), 4.37 (s, 2H0, 2.63 (d, 3H, J=3.3 Hz); LCMS: purity: 94%; MS (m/e):404 (MH⁺). 7.3.736 N4-(4-Chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920396) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(4-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.21 (bs, 1H), 10.00 (bs, 1H), 8.26 (d, 1H, J=4.8Hz), 8.00 (bd, 1H, J=4.2 Hz), 7.77 (dd, 2H, J=2.1 and 7.6 Hz), 7.37 (dd,2H, J=2.1 and 7.6 Hz), 7.17 9m, 3H), 8.63 (dd, 1H, J=1.8 and 8.1 Hz),4.37 (s, 2H), 2.64 (d, 3H, 4.5 Hz); LCMS: purity: 92%; MS (m/e): 402(MH⁺). 7.3.736.1 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920397) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(3,4-dichlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.02 (bs, 1H), 9.76 (bs, 1H), 8.24 (d, 1H, J=4.2Hz), 8.08 (m, 1H), 7.97 (bd, 1H, J=4.8 Hz), 7.77 (m, 1H), 7.55 (d, 1H,J=8.7 Hz), 7.18 (m, 3H), 6.58 (m, 1H), 4.36 (s, 1H), 2.63 (d, 1H, J=2.7Hz); LCMS: purity: 91%; MS: 434 (MH⁺). 7.3.7375-Fluoro-N4-(5-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920398) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(5-methylpyridin-2-yl)-4-pyrimidineamine gave5-fluoro-N4-(5-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.35 (bs, 1H), 10.70 (bs, 1H), 8.58 (s, 1H), 8.42(d, 1H, J=3.0 Hz), 8.12 (bd, 1H, J=9.3 Hz), 8.03 (bd, 1H, J=4.2 Hz),7.82 (d, 1H, J=8.7 Hz), 7.56 (s, 1H), 7.30 (bdd, 1H, J=8.1 Hz), 7.19 (t,1H, J=8.1 Hz), 6.55 (dd, 1H, J=1.8 and 8.1 Hz), 4.41 (s, 2H), 2.63 (d,3H, J=3.6 Hz), 2.36 (s, 3H); LCMS: purity: 99%; MS (m/e): 382 (M⁺).7.3.738 5-Fluoro-N4-(6-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R920399) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(6-methylpyridin-2-yl)-4-pyrimidineamine gave5-fluoro-N4-(6-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.00 (bs, 1H), 9.60 (bs, 1H), 8.25 (s, 1H), 7.95 (m,3H), 7.30 (s, 1H), 7.10 (m, 3H), 6.55 (d, 1H, J=7.2 Hz), 4.40 (s, 2H),2.62 (d, 3H, J=3.6 Hz), 2.45 (s, 3H); LCMS: purity: 92%; MS (m/e): 383(MH⁺). 7.3.739 N4-(5-Chloropyridin-2-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (R920405) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(5-chloropyridin-2-yl)-5-fluoro-4-pyrimidineamine gaveN4-(5-chloropyridin-2-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.04 (bs, 1H), 9.53 (bs, 1H), 8.40 (d, 1H, J=2.4Hz), 8.22 (m, 2H), 7.88 (bd, 1H, J=4.5 Hz), 7.86 (dd, 1H, J=2.4 and 8.7Hz), 7.40 (d, 1H, J=1.8 Hz), 7.19 (m, 2H), 6.51 (bdd, 1H, J=1.2 and 9Hz), 4.38 (s, 2H), 2.64 (d, 3H, J=3.3 Hz); LCMS: purity: 95%; MS (m/e):403 (MH⁺). 7.3.740N4-(6-Chloropyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (R920406) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine gaveN4-(6-chloropyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.72 (s, 1H), 9.38 (s, 1H), 8.93 (t, 1H, J=3.0 Hz),8.28 (m, 1H), 8.18 (d. 1H, J=3.6 Hz), 7.95 (m, 1H), 7.45 (d, 1H, J=8.7Hz), 7.39 (m, 1H), 7.21 (m, 1H), 7.14 (t, 1H, J=4.8 Hz), 6.50 (bdd, 1H,J=7.8 Hz), 4.4 (s, 2H, 2.63 (d, 3H); LCMS: purity: 100%; MS (m/e): 403(MH⁺). 7.3.7415-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(4-methylpyridin-2-yl)-2,4-pyrimidinediamine(R927016) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-methylpyridin-2-yl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(4-methylpyridin-2-yl)-2,4-pyrimidinediamine.LCMS: purity: 95%; MS (m/e): 383 (MH⁺). 7.3.7425-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R920407) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(3-trifluoromethylphenyl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ9.835 (bs, 1H), 9.54 (bs, 1H), 8.20 (d, 1H, J=3.6 Hz), 7.94 (m, 2H),7.78 (bs, 1H), 7.43 (t, 1H, J=8.4 Hz), 7.25 (m, 2H), 7.15 (t, 1H, J=7.5Hz), 7.03 (bd, 1H, J=9.3 Hz), 6.55 (bd, 1H, J=7.5 Hz), 4.36 (s, 2H),2.63 (d, 3H, J=4.5 Hz); LCMS: purity: 91%; MS (m/e): 452 (MH⁺). 7.3.743N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R920408) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineaminegave N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.91 (bs, 1H), 9.64 (bs, 1H), 8.19 (d, 1H, J=3.9 Hz),8.03 (s, 1H), 7.96 (bd, 1H, J=4.8 Hz), 7.46 (m, 1H), 7.36 (d, 1H, J=8.7Hz), 7.27 (bs, 1H), 7.17 (m, 2H), 6.57 (bdd, 1H, J=7.2 Hz), 4.36 (s,1H), 2.62 (d, 3H, J=4.5 Hz); LCMS: purity: 96%; MS (m/e): 448 (MH⁺).7.3.744N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R920410) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineaminegaveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.08 (d, 1H, J=5.4 Hz), 7.99 (d, 1H, J=3.6 Hz), 7.67(dd, 1H, J=2.4 and 9.0 Hz), 7.40 (m, 3H), 7.06 (m, 2H), 6.92 (dd, 1H,J=2.4 and 8.4 Hz), 4.44 (s, 2H), 2.80 (s, 3H); ¹⁹F NMR (CD₃OD): - 16973and - 45983; LCMS: purity: 96%; MS (m/e): 486 (MH⁺). 7.3.745N4-(4-Ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926827) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine gaveN4-(4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 96%; MS: 412 (MH⁺). 7.3.746N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926828) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-amino-6-methoxyphenoxyacetamide with2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.83 (s, 1H), 7.80 (d, 1H, J=4.2 Hz), 7.30 (d, 1H, 2.4Hz), 7.23 (d, 1H, J=2.4 Hz), 7.06 (m, 2H), 6.90 (d, 1H, J=5.7 Hz), 6.73(d, 1H, J=5.2 Hz), 4.32 (s, 2H), 4.22 (s, 4H), 3.86 (s, 3H), 2.83 (s,3H); LCMS: purity: 97%; MS (m/e): 455 (MH⁺). 7.3.7475-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926829) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-amino-4-methoxyphenoxyacetamide with2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.86 (d, 1H, J=4.2 Hz), 7.35 (d, 1H, J=2.4 Hz), 7.19(m, 1H), 7.12 (m, 3H), 6.93 (d, 1H, J=8.7 Hz), 6.52 (m, 1H), 4.37 (s,2H), 3.85 (s, 3H), 2.82 (s, 3H); ¹⁹F NMR (CD₃OD): - 47650; LCMS: purity:100%; MS: 414 (MH⁺). 7.3.748N4-(3-Chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926832) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of 3 N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3-chlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(3-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.12 (s, 1H), 9.93 (s, 1H), 8.27 (d, 1H, J=4.2 Hz),7.98 (d, 1H, J=4.9 Hz), 7.85 (s, 1H), 7.73 (d, 1H, J=8.1 Hz), 7.35 (t,1H, J=8.4 Hz), 7.19 (m, 3H), 6.62 (m, 1H), 4.36 (s, 2H), 2.63 (d, 3H,J=4.2 Hz); LCMS: purity: 95%; MS: 402 (MH⁺). 7.3.7495-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926833) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-4-pyrimidineaminegave5-fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 95%; MS (m/e): 466 (MH⁺). 7.3.7505-Fluoro-N4-(3-hydroxy-4-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926834) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(3-hydroxy-4-methoxyphenyl)-4-pyrimidineamine gave5-fluoro-N4-(3-hydroxy-4-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.70 (bs, 2H), 8.12 (d, 1H, J=4.8 Hz), 7.96 (m, 1H),7.12 (m, 5H), 6.85 (d, 1H, J=8.7 Hz), 6.57 (bd, 1H, J=8.1 Hz), 4.35 (s,2H), 3.74 (s, 3H), 2.63 (d, 3H, J=4.5 Hz); LCMS: purity: 99%; MS (m/e):414 (MH⁺). 7.3.7515-Fluoro-N4-(4-methoxy-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926835) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-methoxy-3-trifluoromethylphenyl)-4-pyrimidineaminegave5-fluoro-N4-(4-methoxy-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.9 Bs, 1H), 9.62 (bs, 1H), 8.17 (d, 1H, J=4.2 Hz),8.04 (bdd, 1H, J=7.2 Hz), 7.82 (t, 1H, 2.7 Hz), 7.18 (m, 3H), 7.11 (t,1H, J=8.1 Hz), 6.55 (bd, 1H, J=6.9 Hz); 4.33 (s, 2H), 3.86 (s, 3H), 2.61(d, 3H, J=4.0 Hz); LCMS: purity: 93%; MS: 466 (MH⁺). 7.3.7525-Fluoro-N4-(4-fluoro-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926838) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-fluoro-3-trifluoromethylphenyl)-4-pyrimidineaminegave5-fluoro-N4-(4-fluoro-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.80 (s, 1H), 9.44 (s, 1H), 8.25 (m, 1H), 8.18 (d,1H, J=3.9 Hz), 8.00 (m, 1H), 7.97 (m, 1H), 7.47 (t, 1H, J=9.6 Hz), 7.26(s, 1H), 7.21 (m, 1H), 7.11 (t, 1H, J=8.4 Hz), 6.51 (bd, 1H, J=9.9 Hz),4.34 (s, 2H), 2.62 (d, 3H, J=4.8 Hz); LCMS: purity: 88%; MS: 454 (MH⁺).7.3.753N4-(3-Chloro-4-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926839) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(3-chloro-4-methylphenyl)-4-pyrimidineamine gaveN4-(3-chloro-4-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.69 (s, 1H), 9.52 (s, 1H), 8.16 (d, 1H, J=4.2 Hz),7.96 (bs, 1H), 7.81 (d, 1H, J=2.1 Hz), 7.67 (bd, 1H, J=8.4 Hz), 7.26 (m,3H), 7.15 (t, 1H, J=8.1 Hz), 6.54 (bd, 1H, J=7.2 Hz), 4.34 (s, 2H), 2.63(d, 3H, J=4.2 Hz), 2.27 (s, 3H); LCMS: purity: 80%; MS (m/e): 415 (M⁺).7.3.754 N4-(2-Chloro-5-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926840) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(2-chloro-5-methylphenyl)-4-pyrimidineamine gaveN4-(2-chloro-5-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.80 (bs, 2H), 8.21 (d, 1H, J=4.8 Hz), 7.92 (d, 1H,J=4.8 Hz), 7.46 (m, 1H), 7.31 (m, 2H), 7.04 (m, 2H), 6.53 (bd, 1H, J=8.1Hz), 4.30 (s, 1H), 2.18 (s, 3H); LCMS: purity: 93%; MS (m/e): 416 (MH⁺).7.3.755 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926830) The reactionofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith isopropylamine (5 equivalents) in the presence ofdiisopropylethylamine (5 equivalents) in MeOH in a sealed tube at 80° C.for 24 hours gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.15 (s, 1H), 8.04 (d, 1H, J=4.2 Hz), 7.77 (d, 1H,J=7.5 Hz), 7.28 (m, 4H), 7.08 (t, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.7 Hz),6.45 (dd, 1H, J=1.8 and 7.8 Hz), 4.30 (s, 2H), 4.20 (s, 4H), 3.92 (m,1H), 1.06 (d, 6H, J=6.6 Hz); LCMS: purity: 95%; MS (m/e): 454 (MH⁺).7.3.756N2-[3-(N-Cyclopropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926848) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewith cyclopropylamine gave5-fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-cyclopropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.17 (bs, 2H), 8.05 (m, 2H), 7.27 (m, 4H), 7.08 (t,1H, J=8.1 Hz), 7.67 (d, 1H, J=8.7 Hz), 6.42 (dd, 1H, J=2.4 and 8.1 Hz),4.3 (s, 2H), 4.2 (bs, 4H), 2.65 (m, 1H), 0.6 (m, 2H), 0.45 (m, 2H);LCMS: purity: 91%; MS (m/e): 452 (MH⁺). 7.3.757N4-(4-Cyano-3-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R926851) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-cyano-3-methylphenyl)-4-pyrimidineamine gaveN4-(4-cyano-3-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.7 (s, 1H), 9.40 (s, 1H), 8.2 (s, 1H), 8.00-7.50 (m,3H), 7.40-7.00 (m, 3H), 6.50 (bm, 1H), 4.35 (s, 2H), 2.60 (s, 3H), 2.35(s, 3H); LCMS: purity: 91%; MS (m/e): 407 (MH⁺). 7.3.7585-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926855) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.04 (bs, 1H), 9.65 (bs, 1H), 8.35 (s, 1H), 8.23 (d,1H, J=3.9 Hz), 8.00 (bd, 1H, J=6.6 Hz), 7.91 (bd, J=3.6 Hz), 7.77 (d,1H, J=8.1 Hz), 7.57 (t, 1H, J=8.1 Hz), 7.23 (m, 2H), 6.95 (t, 1H, J=8.4Hz), 6.46 (bdd, 1H, J=1.8 and 8.1 Hz), 4.22 (s, 2H), 2.62 (d, 3H, 4.2Hz); LCMS: purity: 83%; MS (m/e): 436 (MH⁺). 7.3.7595-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(N-methylphthalimido-4-yl)-2,4-pyrimidinediamine(R926856) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(N-methylphthalimido-4-yl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(N-methylphthalimido-4-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.95 (s, 1H), 9.44 (s, 1H), 8.29 (m, 1H), 8.25 (m,1H), 8.18 (d, 1H, J=1.8 Hz), 7.88 (bd, 1H, J=4.5 Hz), 7.75 (d, 1H, J=6.6Hz), 7.38 (bs, 1H), 7.22 (bd, 1H, J=8.1 Hz), 7.14 (t, 1H, J=7.8 Hz),6.50 (dd, 1H, J=1.8 and 9.0 Hz), 4.28 (s, 2H), 2.99 (s, 3H), 2.60 (d,3H, J=4.5 Hz); LCMS: purity: 92%; MS (m/e): 451 (MH⁺). 7.3.760N4-(2,5-Dimethoxy-4-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926859) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide withN4-(2,5-dimethoxy-4-chlorophenyl)-2-chloro-5-fluoro-4-pyrimidineaminegaveN4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.05 (d, 1H, J=5.4 Hz), 7.29 (s, 1H), 7.24 (t, 1H,J=8.1 Hz), 7.18 (s, 1H), 7.02 (t, 1H, J=2.1 Hz), 6.92 (dd, 1H, J=1.8 and8.1 Hz), 6.83 (dd, 1H, J=2.4 and 8.4 Hz), 4.29 (s, 2H), 3.81 (s, 3H),3.59 (s, 3H), 2.81 (s, 3H); LCMS: purity: 96%; MS (m/e): 460 (MH)-; 462(MH⁼). 7.3.761 5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926862) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4-pyrimidineaminegave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.95 (s, 1H), 9.41 (s, 1H), 8.57 (s, 1H), 8.33 (s,1H), 8.23 (d, 1H, J=3 Hz), 7.83 (s and d, 2H), 7.22 (m, 2H), 7.02(t, 1H,J=8.7 Hz), 6.48 (1H, J=2.4 and 7.5 Hz), 4.27 (s, 2H), 3.80 (s, 3H), 2.60(d, 3H, J=4.8 Hz); ¹⁹F NMR (DMSO-d₆): - 17446; LCMS: purity: 94%; MS(m/z): 494 (MH⁺). 7.3.7625-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926870) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-4-pyrimidineaminegave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 86%; MS (m/e): 512 (MH+). 7.3.763N4-[3-(2-(3-Chlorophenyl)-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926871) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-[3-(2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl)phenyl]-4-pyrimidineaminegaveN4-[3-(2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 100%; MS (m/e): 546 (MH⁺). 7.3.7645-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine (R926879)In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-trifluoromethoxyphenyl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.05 (bs, 1H), 9.74 (bd, 1H, J=1.5 Hz), 8.22 (d, 1H,J=4.2 Hz), 7.99 (bd, 1H, J=4.5 Hz), 7.86 (m, 2H), 7.32 (d, 2H, J=8.1Hz), 7.26 (s, 1H), 7.16 (m, 2H), 6.58 (m, 1H), 4.36 (s, 2H), 2.65 (bd,3H); LCMS: purity: 92%; MS (m/e): 452 (MH⁺). 7.3.7655-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethylphenyl]-2,4-pyrimidinediamine (R926880)In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(4-trifluoromethylphenyl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethylphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.10 (bs, 1H), 9.72 (d, 1H, J=1.2 Hz), 8.26 (d, 1H,J=4.2 Hz), 8.00 (m, 3H), 7.65 (d, 2H, J=8.1 Hz), 7.31 (bs, 1H), 7.17 (d,2H, J=5.4 Hz), 6.59 (m, 1H), 4.36 (s, 2H), 2.62 (d, 3H, J=4.8 Hz); LCMS:purity: 92%; MS (m/e): 436 (MH⁺). 7.3.766N4-(4-Chloro-3-trifluoromethylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R926881) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineaminegaveN4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.20 (bs, 1H), 9.81 (bs, 1H), 8.28 (d, 1H, J=3.9Hz), 8.23 (bdd, 1H, J=8.7 Hz), 8.11 (d, 1H, J=2.4 Hz), 7.98 (bd, 1H,J=4.5 Hz), 7.65 (d, 1H, J=8.7 Hz), 7.17 (m, 3H), 6.59 (m, 1H), 4.35 (s,2H), 2.63 (d, 3H, J=4.2 Hz); LCMS: purity: 87%; MS (m/e): 470 (MH⁺).7.3.7675-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine(R926883) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of 3 N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine gave5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.17 (bs, 1H), 9.83 (s, 1H), 8.24 (d, 1H, J=4.8 Hz),8.17 (m, 1H), 7.94 (m, 2H), 7.86 (m, 1H), 7.39 (d, 1H, J=9.3 Hz), 7.25(s, 1H), 7.16 (m, 2H), 6.60 (m, 1H), 6.50 (d, 1H, J=9.6 Hz), 4.32 (s,2H), 2.60 (d, 3H, J=3.6 Hz); LCMS: purity: 98%; MS 9m/e): 436 (MH⁺).7.3.768 5-Fluoro-N4-(2-methoxypyridin-5-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (R926886) In likemanner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-5-fluoro-N4-(2-methoxypyridin-5-yl)-4-pyrimidineamine gave5-fluoro-N4-(2-methoxypyridin-5-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.36 (bs, 1H), 9.19 (s, 1H), 8.59 (d, 1H, J=3 Hz),8.05 (m, 3H), 7.38 (m, 1H), 7.24 (bd, 1H, J=8.1 Hz), 7.08 (t, 1H, J=8.4Hz), 6.79 (d, 1H, J=8.7 Hz), 6.46 (dd, 1H, J=2.4 and 7.8 Hz), 4.34 (s,2H), 3.82 (s, 3H), 2.63 (d, 3H, J=4.5 Hz); LCMS: purity: 95%; MS (m/e):399 (MH⁺). 7.3.7695-Fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R927023) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with 2-chloro-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-4-pyrimidineamine gave5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.65 (bs, 1H), 9.45 (bs, 1H), 8.55 (s, 1H), 8.12 (d,1H, J=3.6 Hz), 7.99 (m, 2H), 7.28 (m, 1H), 7.19 (m, 2H), 7.11 (t, 1H,J=8.4 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.52 (m, 2H), 4.35 (s, 2H), 4.23 (t,2H, J=5.1 Hz), 3.69 (t, 2H, J=4.5 Hz), 2.63 (d, 3H, J=2.7 Hz); LCMS:purity: 95%; MS (m/e): 429 (MH⁺). 7.3.770N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R920404) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(2,6-dimethoxypyridin-3-yl]-5-fluoro-4-pyrimidineamine gaveN4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.05 (d, 1H, J=1.8 Hz), 8.62 (s, 1H), 8.01 (d, 1H,J=3.6 Hz), 7.91 (bd, 1H, J=4.8 Hz), 7.77 (m, 1H), 7.18 (m, 2H), 6.96 (t,1H, J=8.1 Hz), 6.40 (d, 2H, J=8.1 Hz), 4.29 (s, 2H), 3.86 (s, 3H), 3.85(s, 3H), 2.63 (d, 3H, J=4.5 Hz); LCMS: purity: 86%; MS (m/e): 429 (MH⁺).7.3.771N4-(4-Chloro-3-methoxyphenyl))-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R927042) In like manner to preparation ofN4-(3,4-difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminethe reaction of N-methyl 3-aminophenoxyacetamide with2-chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine gaveN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.89 (bs, 1H), 9.66 (bs, 1H), 8.20 (d, 1H, J=4.2 Hz),7.95 (bd, 1H), 7.48 (m, 2H), 7.33 (d, 1H, J=9.1 Hz), 7.26 (bs, 1H), 7.17(m, 2H), 6.57 (bd, 1H, J=7.8 Hz), 4.34 (s, 2H), 3.72 (s, 3H), 2.62 (d,3H); LCMS: purity: 97%; MS (m/e): 432 (MH⁺). 7.3.772N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R920411) A solution of2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine(1.1 equivalents) and 3-hydroxyaniline (1 equivalent) in a sealed tubewas heated at 100° C. for 24 hours. The resulting solution was dilutedwith EtOAc and the solid obtained was filtered, washed with a mixture ofEtOAc:n-hexanes (1:1; v/v), dried and analyzed to giveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine.¹H NMR (CD₃OD): δ8.02 (d, 1H, J=5.1 Hz), 7.98 (d, 1H, J=3.0 Hz), 7.72(dd, 1H, J=3.0 and 9.3 Hz), 7.42 (dd, 1H, J=1.2 and 9.0 Hz), 7.22 (t,1H, J=8.4 Hz), 6.85 (m, 2H), 6.73 (dd, 1H, J=2.4 and 8.7 Hz); ¹⁹F NMR(CD₃OD): - 16967 and - 46027; LCMS: purity: 97%; MS (m/e): 415 (MH⁺).7.3.7735-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926866) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-4-pyrimidineaminegave5-fluoro-N2-(3-hydroxyphenyl)-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.72 (bs, 1H), 7.96 (bd, 3H), 7.85 (m, 2H), 7.56 (m,4H), 7.14 (d, 1H, J=2.1 Hz), 6.91 (m, 2H), 6.28 (dd, 1H, J=1.8 and 6.9Hz); LCMS: purity: 80%; MS (m/e): 441 (MH⁺). 7.3.774N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926794) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineaminegaveN4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.LCMS: purity: 85%; MS (m/e): 377 (MH⁺). 7.3.7755-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R926885) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine gave5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.99 (bs, 1H), 9.61 (bs, 1H), 8.21 (d, 1H, J=4.2 Hz),7.93 (bd, 1H, J=7.5 Hz), 7.78 (s, 1H), 7.43 (t, 1H, J=8.4 Hz), 7.03 (m,4H), 6.43 (m, 1H); ¹⁹F NMR (DMSO-d₆): -16097; LCMS: purity: 85%; MS(m/e): 381 (MH⁺). 7.3.776N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926887) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine gaveN4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.98 (bs, 2H), 8.20 (d, 1H, J=5.4 Hz), 7.72 9m, 1H),6.90 (t, 1H, J=7.8 Hz), 6.81 (m, 2H), 6.42 (m, 2H), 3.88 (s, 3H), 3.86(s, 3H); LCMS: purity: 94%; MS (m/e): 358 (MH⁺). 7.3.7775-Fluoro-N2-(3-hydroxyphenyl)-N4-(5-methylpyridin-2-yl)-2,4-pyrimidinediamine(R927017) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-5-fluoro-N4-(5-methylpyridin-2-yl)-4-pyrimidineamine gave5-fluoro-N2-(3-hydroxyphenyl)-N4-(5-methylpyridin-2-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.39 (bs, 1H), 10.59 (bs, 1H), 8.58 (s, 1H0, 8.41(d, 1H, J=3 Hz), 8.12 (d, 1H, J=8.7 Hz), 7.82 (d, 1H, J=8.7 Hz), 7.29(s, 1H), 7.16 (d, 1H, J=9 Hz), 7.05 (t, 1H, J=8.4 Hz), 6.38 (dd, 1H, 1.2and 6.9 Hz); LCMS: purity: 99%; MS (m/e): 312 (MH⁺). 7.3.778N4-(6-Chloropyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R927018) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine gaveN4-(6-chloropyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.10 (bs, 1H), 9.64 (bs, 1H), 8.85 (m, 1H), 8.30 (m,2H), 8.22 (d, 1H, J=4.2 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.01 (m, 3H), 6.42(bd, 1H, J=8.4 Hz); LCMS: purity: 93%; MS (m/e): 332 (MH⁺). 7.3.7795-Fluoro-N2-(3-hydroxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine(R927019) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine gave5-fluoro-N2-(3-hydroxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.50 (s, 1H), 10.14 (s, 1H), 8.29 (d, 1H, J=4.8 Hz),8.14 (d, 1H, J=1.8 Hz), 7.96 (d, 1H, J=9.3 Hz), 7.83 (dd, 1H, J=2.4 and9.0 Hz), 7.40 (d, 1H, J=8.7 Hz), 7.04 (t, 1H, J=8.1 Hz), 6.93 (m, 2H),6.52 (m, 2H); LCMS: purity: 93%; MS (m/e): 365 (MH⁺). 7.3.780N4-(5-Chloropyridin-2-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R927020) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(5-chloropyridin-2-yl)-5-fluoro-4-pyrimidineamine gaveN4-(5-chloropyridin-2-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.80 (bs, 1H), 9.77 (bs, 1H), 8.45 (bd, 1H), 8.26(d, 1H, J=3.9 Hz), 8.15 (d, 1H, J=8.7 Hz), 7.85 (dd, 1H, J=2.4 and 8.7Hz), 7.06 (m, 3H), 6.43 (bd, 1H, J=7.2 Hz); LCMS: purity: 97%; MS (m/e):332 (MH⁺). 7.3.781N4-(4-Chloro-2,5-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-primidinediamine(R926860) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 3-hydroxyaniline with2-chloro-N4-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineaminegaveN4-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-primidinediamine.¹H NMR (CD₃OD): δ7.96 (d, 1H, J=4.8 Hz), 7.66 (s, 1H), 7.13 (s, 1H),7.07 (t, 1H, J=8.7 Hz), 8.86 (m, 2H), 6.57 (dd, 1H, J=3.2 and 8.1 Hz),3.48 (s, 3H), 3.66 (s, 3H); ¹⁹F NMR (CD₃OD): - 46968. 7.3.782N4-(4-Chlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R927026) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 5-amino-2-methoxycarbonylbenzofuran with2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(4-chlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.28 (bs, 1H), 10.18 (bs, 1H), 8.25 (d, 1H, J=4.5Hz), 7.96 (bs, 1H), 7.84 (m, 1H), 7.67 (m, 3H), 7.57 (m, 1H), 7.37 (bd,2H, J=9.0 Hz), 3.88 (s, 3H); LCMS: purity: 96%; MS (m/e): 413 (MH⁺).7.3.783N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine(R927027) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 5-amino-2-methoxycarbonylbenzofuran with2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gaveN4-(3,4-dichlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.70 (bs, 1H), 9.50 (bs, 1H), 8.20 (d, 1H, J=4.5 Hz),8.09 (m, 1H), 7.80 (m, 3H), 7.62 (m, 2H), 7.53 (m, 1H), 7.38 (m, 1H),3.88 (s, 3H); LCMS: purity: 94%; MS (m/e): 448 (MH⁺). 7.3.7845-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926863) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-methoxycarbonyl-5-trifluoromethylaniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.98 (s, 1H), 9.52 (s, 1H), 8.53 (s, 1H), 8.38 (s,1H), 8.20 (d, 1H, J=4.2 Hz), 7.69 (s, 1H), 7.27 (d, 1H, J=8.1 Hz), 7.14(s, 1H), 7.05 (t, 1H, 7.8 Hz), 6.49 (dd, 1H, J=1.8 and 8.4 Hz), 3.80 (s,3H); LCMS: purity: 82%; MS (m/e): 423 (MH⁺). 7.3.785N2-(4-Chloro-2,5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926857) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 4-chloro-2,5-dimethoxyaniline gaveN2-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.04 (d, 1H, J=5.4 Hz), 7.46 (s, 1H), 7.17 (m, 2H),7.03 (m, 2H), 6.72 (dd, 1H, J=1.8 and 7.8 Hz), 3.85 (s, 3H), 3.52 (s,3H); LCMS: purity: 98%; MS (m/e): 390 (MH⁺). 7.3.786N2-(3-Bromo-5-trifluorophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926846) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-bromo-5-trifluoromethylaniline gaveN2-(3-bromo-5-trifluorophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.70 (s, 1H), 9.36 (s, 1H), 9.34 (s, 1H), 8.31 (s,1H), 8.18 (d, 1H, J=3.6 Hz), 8.02 (s, 1H), 7.35 (s, 1H), 7.28 (bd, 1H,J=7.2 Hz), 7.11 (t, 1H, J=8.4 Hz), 7.02 (m, 1H), 6.49 (dd, 1H, J=1.8 and7.8 Hz); LCMS: purity: 94%; MS (m/e): 442 (MH⁺). 7.3.7875-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1H-pyrazol-3-yl)phenyl]-2,4-pyrimidinediamine(R926841) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-(1H-pyrazol-3-yl)aniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1H-pyrazol-3-yl)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 84%; MS 363 (MH⁺) 7.3.7885-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926842) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-(tetrazol-5-yl)aniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.05 (bs, 1H), 9.80 (bs, 1H), 8.27 (s, 1H), 8.23 (d,1H, J=3.3 Hz), 7.86 (d, 1H, J=8.1 Hz) 7.65 (d, 1H, J=6.9 Hz), 7.44 (t,1H, J=7.5 Hz), 7.19 (m, 2H), 6.93 (t, 1H, J=7.5 Hz), 6.49 (dd, 1H, J=2.4and 8.1 Hz); LCMS: purity: 89%; MS (m/e): 364 (MH⁺). 7.3.7895-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926831) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-(1,3-oxazol-5-yl)aniline gave5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 76%; MS (m/e): 364 (MH⁺). 7.3.790N2-(3-Chloro-4-trifluoromethylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinedimine(R926844) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-chloro-4-trifluoromethoxyaniline gaveN2-(3-chloro-4-trifluoromethylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinedimine.¹H NMR (DMSO-d₆): δ9.70 (bs, 1H), 9.48 (bs, 1H), 8.15 (bd, 1H, J=3.6Hz), 8.06 (s, 1H), 7.62 (dd, 1H, J=2.4 and 9.3 Hz), 7.37 (d, 1H, J=9.0Hz), 7.20 9m, 1H), 7.11 (m, 3H), 6.53 (bd, 1H, J=8.1 Hz); LCMS: purity:93%; MS (m/e): 414 (MH⁺). 7.3.7915-Fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine(R926843) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with3-(tetrazol-5-yl)aniline gave5-fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.91 (s, 1H), 9.74 (s, 1H), 8.29 (s, 1H), 8.18 (d,1H, J=4.5 Hz), 7.76 (bdd, 1H, J=1.5 and 8.1 Hz), 7.64 (d, 1H, J=8.1 Hz),7.46 (t, 1H, J=8.1 Hz), 7.29 (m, 1H), 7.13 (dd, 1H, J=2.4 and 8.7 Hz),6.64 (d, 1H, J=8.7 Hz), 4.11 (m, 4H); LCMS: purity: 91%; MS (m/e): 407(MH⁺). 7.3.792N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine(R926845) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with4-methoxy-2-methylaniline gaveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.30 (bs, 1H), 9.10 (bs, 1H), 8.22 (d, 1H, J=5.1Hz), 7.55 (m, 1H), 7.15 (m, 1H), 7.07 (m, 1H), 6.92 (m, 2H), 6.82 (d,1H, J=8.7 Hz), 4.22 (bs, 4H), 3.80 (s, 3H), 2.15 (s, 3H); LCMS: purity:94%; MS (m/e): 383 (MH⁺). 7.3.793N2-[5-(N-Aminocarbonylmethylene-2-oxo-1,3-oxazol-3(2H)-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrmidinediamine(R926847) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with2-[5-amino-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide gaveN2-[5-(N-aminocarbonylmethylene-2-oxo-1,3-oxazol-3(2H)-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrmidinediamine.¹H NMR (CD₃OD): δ7.95 (d, 1H, J=8.4 Hz), 7.32 (dd, 1H, J=2.4 and 8.1Hz), 7.24 (d, 1H, J=2.4 Hz), 7.19 (m, 2H), 6.95 (dd, 1H, J=2.7 and 9Hz), 6.80 (d, 1H, J=9 Hz), 4.51 (s, 2H), 4.21 (m, 4H). 7.3.794N2-[3-(2-Ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926874) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineaminewith 3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)aniline gaveN2-[3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.52 (s, 1H), 9.31 (s, 1H), 9.28 (s, 1H), 8.30 (s,1H), 8.12 (d, 1H, J=3.6 Hz), 8.00 (m, 1H), 7.49 (d, 1H, J=7.5 Hz), 7.42(d, 1H, J=8.4 Hz), 7.30 (m, 1H), 7.12 (bs, 1H), 7.03 (t, 1H, J=8.1 Hz),6.46 (m, 1H), 4.21 (s, 2H), 4.15 (q, 2H, J=6.9 Hz), 1.19 (t, 3H, J=7.2Hz); LCMS: purity: 90%; MS (m/e): 451 (MH⁺). 7.3.795N2,N4-Bis(3-boronylphenyl)-5-fluoro-2,4-pyrimidinediamine (R926836) Amixture of 2,4-dichloro-5-fluoro-pyrimidine (1 equivalents) and3-aminophenylboronic acid (3 equivalents) in MeOH was heated in a sealedtube at 100° C. for 24 hours. The resulting mixture was cooled to roomtemperature, acidified with 2N HCl and the solid obtained was filtered,washed with water, dried and analyzed to giveN2,N4-sis(3-boronylphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ10.40 (s, 1H), 10.07 (s, 1H), 8.25 (d, 8.4 Hz), 7.85 (s,1H), 7.73 (d, 1H, J=7.5 Hz), 7.63 (bt, 3H), 7.48 (d, 1H, J=6.9 Hz), 7.30(t, 1H, J=8.4 Hz), 7.12 (t, 1H, J=2.5 Hz); LCMS: purity: 85%; MS (m/e):368 (MH⁺). 7.3.796.N2-(3-Boronylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926837) In like manner to the preparation ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine,the reaction of2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with3-aminophenylboronic acid gaveN2-(3-boronylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 99%; MS (m/e): 383 (MH⁺). 7.3.797(±)-N4-(3,4-Difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R927030) A mixture of equivalent amount of2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine and(±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran in MeOH was shakenin a sealed tube at 80° C. for 48 h, cooled to room temperature anddiluted with a mixture of n-hexanes:EtOAc (1:1; v/v). The resultingsolid formed was filtered, washed with a mixture of EtOAc:n-hexanes(1:1; v/v), dried and analyzed to give(±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.21 (bs, 1H), 9.80 (bs, 1H), 8.20 (d, 1H, J=4.8Hz), 7.94 (bs, 1H), 7.43 (m, 3H0, 7.15 (bd, 1H, J=8.4 Hz), 6.81 (d, 1H,J=8.1 Hz), 5.35 (dd, 1H, J=6.0 and 6.3 Hz), 3.69 (s, 3H), 3.52 (dd, 1H,J=10.5), 3.22 (dd, 1H, J=9.0 and 6.0 Hz); LCMS: purity: 99%; MS (m/e):417 (MH⁺). 7.3.798(±)-N4-(4-Chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R927024) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gave(±)-N4-(4-chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.29 (bs, 1H), 9.89 (bs, 1H), 8.21 (d, 1H, J=4.8Hz), 7.69 (m, 2H), 7.38 (m, 3H), 7.13 (bd, 1H, J=8.1 Hz), 6.83 (d, 1H,J=8.4 Hz), 5.36 (dd, 1H, J=6.3 and 5.7 Hz), 3.70 (s, 3H), 3.52 (dd, 1H,J=10.5 Hz), 3.20 (dd, 1H, J=5.4 and 5.7 Hz); LCMS: purity: 98%; MS(m/e): 415 (MH⁺). 7.3.799(±)-N4-(3,4-Dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine(R927031) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gave(±)-N4-(3,4-dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.13 (bs, 1H), 9.70 (bs, 1H), 8.21 (d, 1H, J=4.8Hz), 8.04 (d, 1H, J=2.4 Hz), 7.68 (m, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.37(bs, 1H), 7.19 (m, 1H), 6.80 (d, 1H, J=8.7 Hz), 5.35 (dd, 1H, J=6.6 Hz),3.69 (s, 3H), 3.53 (dd, 1H, J=10.5 and 11.1 Hz), 3.21 (dd, 1H, J=6.0Hz); LCMS: purity: 100%; MS (m/e): 450 (MH⁺). 7.3.800(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-2,4-pyrimidinediamine(R927032) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine gave(±)--N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.03 (bs, 2H), 8.18 (d, 1H, J=4.8 Hz), 7.68 (bd, 1H,J=8.1 Hz), 7.27 (bs, 1H), 6.98 (bd, 1H, J=8.1 Hz), 6.69 (d, 1H, J=8.7Hz), 6.44 (d, 1H, J=8.1 Hz), 5.33 (dd, 1H, J=5.7 Hz), 3.88 (s, 3H), 3.86(s, 3H), 3.69 (s, 3H), 3.42 (dd, 1H, J=10.8 and 11.1 Hz), 3.10 (dd, 1H,J=6.3 and 6.6 Hz); LCMS: purity: 99%; MS (m/e): 442 (MH⁺). 7.3.801(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927025) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-4-pyrimidineaminegave(±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.10 (bs, 1H), 9.70 (bs, 1H), 8.46 (m, 1H), 8.13 (d,1H, J=4.8 Hz), 7.92 (m, 1H), 7.41 (bs, 1H), 7.12 (bdd, 1H, J=8.4 Hz),6.79 (m, 2H), 5.35 (dd, 1H, J=5.7 and 6.0 Hz), 4.24 (t, 2H, J=5.1 Hz),3.70 (s, 3H), 3.69 (t, 2H, J=5.1 Hz), 3.52 (dd, 1H, J=11.1 Hz), 3.24(dd, 1H, J=6.6 Hz); LCMS: purity: 92%; MS (m/e): 442 (MH⁺). 7.3.802(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluorophenyl)-2,4-pyrimidinediamine(R927028) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-5-fluoro-N4-(3-trifluorophenyl)-4-pyrimidineamine gave(±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluorophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.32 (bs, 1H), 9.90 (bs, 1H), 8.23 (d, 1H, J=4.8Hz), 7.80 (bd, 1H, J=6.9 Hz), 7.73 (bs, 1H), 7.43 (t, 1H, J=8.1 Hz),7.36 (bs, 1H), 7.16 (m, 2H), 6.79 (d, 1H, J=8.1 Hz), 5.33 (dd, 1H, J=6.0and 6.6 Hz), 3.69 (s, 3H), 3.51 (dd, 1H, J=10.5 Hz), 3.20 (dd, 1H, J=6.0Hz); LCMS: purity: 98%; MS (m/e): 465 (MH⁺). 7.3.803(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927029) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineaminegave(±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.36 (bs, 1H), 9.93 (bs, 1H), 8.22 (d, 1H, J=4.8Hz), 7.91 (bs, 1H), 7.38 (m, 3H), 7.15 9bd, 1H, J=8.7 Hz), 6.79 (d, 1H,J=6.0 Hz), 5.33 (dd, 1H, J=6.3 and 6.6 Hz), 3.69 (s, 3H), 3.50 (dd, 1H,J=10.5 and 10.8 Hz), 3.22 (dd, 1H, J=6.0 Hz); LCMS: purity: 100%; MS(m/e): 461 (MH⁺). 7.3.804(±)-N4-(3,4-Difluorophenyl)-5-fluoro-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine(R927035) A mixture of(±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine,methylamine Hydrogen Chloride (5 equivalents) and diisopropylethylamine(5 equivalents) in MeOH was shaken in a sealed tube at 80° C. for 24 h.The resulting solution was diluted with water and the precipitateobtained was filtered, washed with water, dried and analyzed to afford(±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.46 (s, 1H), 9.07 (s, 1H), 8.05 (m, 3H), 7.48 (m,2H), 7.35 (m, 1H), 7.22 (m, 1H), 6.72 (d, 1H, J=8.1 Hz), 5.07 (dd, 1H,J=6.6 and 6.3 Hz), 3.40 (dd, 1H), 3.15 (dd, 1H), 2.60 (d, 3H, J=4.5 Hz);LCMS: purity: 98%; MS (m/e): 416 (MH⁺). 7.3.805(±)-N4-(4-Chlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927036) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(±)-N4-(4-chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminegave(±)-N4-(4-chlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.40 (s, 1H), 9.02 (s, 1H), 8.05 (m, 2H), 7.84 (dd,2H, J=2.7 and 9.3 Hz), 7.51 (bs, 1H), 7.32 (bd, 2H, J=8.7 Hz), 7.23 (bd,1H, J=8.7 Hz), 6.72 (d, 1H, J=8.7 Hz), 5.07 (dd, 1H, J=6.0 and 6.3 Hz),3.39 (dd, 1H), 3.17 (dd, 1H), 2.60 (d, 3H, J=4.8 Hz); LCMS: purity: 99%;MS (m/e): 414 (MH⁺). 7.3.806(±)-N4-(3,4-Dichlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927037) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(±)-N4-(3,4-dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminegave(±)-N4-(3,4-dichlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ9.52 (s, 1H), 9.09 (s, 1H), 8.08 (m, 3H), 7.76 (bd,1H, J=9.3 Hz), 7.50 (d, 1H, J=9.0 Hz), 7.43 (bs, 1H), 7.24 (bd, 1H,J=8.7 Hz), 6.73 (d, 1H, J=8.1 Hz), 5.07 (dd, 1H, J=6.3 and 6.6 Hz), 3.39(dd, 1H, J=10.5 Hz), 3.15 (dd, 1H, J=6.3 Hz), 2.60 (d, 3H, J=4.8 Hz);LCMS: purity: 99%; MS (m/e): 450 (MH⁺). 7.3.807(±)-N4-(2,6-Dimethoxypyridin-3-yl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927038) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(±)-N4-(2,6-dimethoxypyridin-3-yl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminegave(+)-N4-(2,6-dimethoxypyridin-3-yl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.98 (d, 1H, J=8.1 Hz), 7.81 (d, 1H, J=3.6 Hz), 7.39(bd, 1H, J=2.4 Hz), 7.06 (dd, 1H, J=2.4 and 8.7 Hz), 6.72 (d, 1H, J=8.1Hz), 6.31 (d, 1H, J=8.7 Hz), 5.07 (dd, 1H, J=6.3 Hz), 3.96 (s, 3H), 3.93(s, 3H), 3.46 (dd, 1H, J=7.8 and 10.5 Hz), 3.19 (dd, 1H, J=5.7 and 6.3Hz), 2.77 (d, 3H, J=4.8 Hz); LCMS: purity: 98%; MS (m/e): 441 (MH⁺).7.3.808(±)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-2,4-pyrimidinediamine(R927039) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-2,4-pyrimidinediaminegave(±)-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.26 (s, 1H), 8.99 (s, 1H), 8.50 (bd, 1H, J=3.0 Hz),8.02 (bd, 2H, J=3.6 Hz), 7.94 (dd, 2H, J=2.7 and 5.1 Hz), 7.52 (bs, 1H),7.20 (bd, 1H, J=8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.67 (d, 1H, J=8.7 Hz),5.05 (dd, 1H, J=6.3 and 6.6 Hz), 4.80 (t, 1H), 4.23 (t, 2H, J=5.1 Hz),3.69(q, 2H, J=5.4 Hz), 3.40 (dd, 1H), 3.15 (dd, 1H, J=6.3 and 9.9 Hz),2.60 (d, 3H, J=4.5 Hz); LCMS: purity: 86%; MS (m/e): 441 (MH⁺). 7.3.809(±)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R927040) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediaminegave(±)-N2-[2,3-dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.LCMS: purity: 94%; MS (m/e): 464 (MH⁺). 7.3.810(±)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-N4-(3,4-difluoromethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927041) In like manner to the preparation of(±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine,the reaction of methyl amine Hydrogen Chloride with(±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediaminegave(±)-N2-[2,3-dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-N4-(3,4-difluoromethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.1H NMR (DMSO-d₆): d 9.46 (s, 1H), 9.05 (s, 1H), 8.05 (m, 3H), 7.43 (m,2H), 7.31 (d, 1H, J=8.7 Hz), 7.23 (bd, 1H, J=7.5 Hz), 6.70 (d, 1H, J=9.0Hz), 5.04 (dd, 1H, J=6.6 Hz), 3.40 (dd, 1H), 3.14 (dd, 1H, J=5.7 and 6.6Hz), 2.60 (d, 3H, J=3.9 Hz); LCMS: purity: 94%; MS (m/e): 460 (MH⁺).7.3.811N2-(4-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926238) The reaction ofN2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith LiOH in THF:H₂O at room temperature gaveN2-(carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.16 (d, 1H, J=4.8 Hz), 7.37 (bd, 2H, J=9 Hz), 7.259d, 1H, J=3Hz), 7.08 (m, 1H), 6.83 (m, 3H), 4.64 (s, 2H), 4.23 (s, 4H);LCMS: ret. time: 19.15 min.; purity: 100%; MS (m/e): 413 (MH⁺). 7.3.812N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt (R920395) To a solution ofN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(1 equivalent) in MeOH at 0° C. was added HCl (4M, dioxane, 1.1equivalents) dropwise and shaken for 5 minutes. The resulting solutionwas diluted with EtOAc and the solid obtained was filtered washed withEtOAc, dried and analyzed to giveN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt. ¹H NMR (DMSO-d₆): δ9.80 (bs, 2H), 8.12 (d, 1H,J=4.8 Hz), 7.89 (bd, 1H, J=4.5 Hz), 7.18 (m, 3H), 8.24 (m, 2H), 6.60(bd, 2H, J=8.1 Hz), 4.36 (s, 2H), 4.10 (t, 2H, J=3.9 Hz), 3.27 (t, 2H,J=3.9 Hz), 2.62 (d, 3H, J=4.5 Hz); LCMS: purity: 98%, MS (m/e): 425(MH⁺). 7.3.813N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineTrifluoro Acetic Acid Salt (R926826) In like manner to the synthesis ofN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHydrogen Chloride Salt the reaction ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewith trifluoroacetic acid gaveN4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineTrifluoro Acetic Acid Salt. ¹H NMR (DMSO-d₆): δ9.40 (bs, 1H), 9.36 (bs,1H), 8.07 (d, 1H, J=4.2 Hz), 7.94 (bd, 1H), 7.22 (m, 4H), 7.11 (t, 1H,J=7.5 Hz), 6.79 (d, 1H, J=8.7 Hz), 6.51 (bd, 1H, J=7.5 Hz), 4.33 (s,2H), 4.21 (bs, 4H), 2.63 (d, 3H, 3.3 Hz). 7.3.8145-Fluoro-N4-[(1H)-indol-6-yl]-N2-[4-methoxy-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926752) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and4-methoxy-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toproduce5-fluoro-N4-[(1H)-indol-6-yl]-N2-[4-methoxy-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.83 (d, 1H, J=3.6 Hz), 7.73 (d, 1H, J=0.9 Hz), 7.49(d, 1H, J=8.1 Hz), 7.39 (d, 1H, J=3.0 Hz), 7.20 (d, 1H, J=3.6 Hz), 7.15(dd, 1H, J=1.8 and 8.1 Hz), 7.05 (dd, 1H, J=2.1 and 8.7 Hz), 6.81 (d,1H, J=8.7 Hz), 6.41 (d, 1H, J=4.2 Hz), 4.09 (s, 2H), 3.81 (s, 3H), 2.76(s, 3H); LCMS: purity: 100%; MS (m/e): 437(MH⁺). 7.3.8155-Fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926753) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to produce5-fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.95 (bs, 1H), 9.83 (bs, 1H), 9.38 (bs, 1H), 8.17(d, 1H, J=4.4 Hz), 7.97 (d, 1H, J=4.8 Hz), 7.24-7.17 (m, 2H), 7.16 (d,1H, J=8.4 Hz), 7.10 (dd, 1H, J=1.8 and 8.4 Hz), 7.03 (d, 1H, J=2.4 Hz),7.00 (d, 1H, J=9.0 Hz), 6.61 (d, 1H, J=8.7 Hz), 4.34 (s, 2H), 2.63 (d,3H, J=4.5 Hz), 2.08 (s, 3H); LCMS: purity: 96%; MS (m/e): 398(MH⁺).7.3.816 5-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926754) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to produce5-fluoro-N4-(3-dihydroxyborylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.38 (bs, 1H), 9.22 (bs, 1H), 8.08 (d, 1H, J=3.6Hz), 8.06-7.81 (m, 4H), 7.51 (d, 1H, J=8.1 Hz), 7.33-7.28 (m, 3H), 7.06(t, 1H, J=8.1 Hz), 6.44 (dd, 1H, J=2.4 and 7.5 Hz), 4.33 (s, 2H), 2.63(d, 3H, J=4.8 Hz); LCMS: purity: 95%; MS (m/e): 412(MH⁺). 7.3.8175-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926755) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and3-hydroxyaniline were reacted to produce5-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.68 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 1H), 8.10(d, 1H, J=3.9 Hz), 7.88-7.80 (m, 2H), 7.54 (d, 1H, J=7.2 Hz), 7.31 (t,1H, J=7.2 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.98-6.93 (m, 2H), 6.35 (d, 1H,J=8.4 Hz); LCMS: purity: 96%; MS (m/e): 341(MH⁺). 7.3.818N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyborylphenyl)-2,4-pyrimidinediamine(R926756) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and3,4-ethylenedioxyaniline were reacted to produceN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyborylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.46 (bs, 1H), 9.11 (bs, 1H), 8.05 (d, 1H, J=4.2Hz), 7.95 (bs, 1H), 7.88 (s, 1H), 7.78 (d, 1H, J=7.5 Hz), 7.52 (d, 1H,J=7.5 Hz), 7.29 (t, 1H, J=7.5 Hz), 7.16 (s, 1H), 7.02 (d, 1H, J=8.7 Hz),6.65 (d, 1H, J=8.7 Hz), 3.40 (s, 4H); LCMS: purity: 98%; MS (m/e):383(MH⁺). 7.3.8195-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926757) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toproduce5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.32 (s, 1H), 9.17 (s, 1H), 9.04 (s, 1H), 8.04 (d,1H, J=4.2 Hz), 7.76 (d, 1H, J=4.8 Hz), 7.32 (td, 2H, J=1.8 and 8.1 Hz),7.13-7.04 (m, 3H), 6.95 (d, 1H, J=8.4 Hz), 6.46 (dd, 1H, J=1.8 and 8.4Hz), 4.31 (s, 2H), 2.65 (d, 3H, J=4.8 Hz), 2.14 (s, 3H); LCMS: purity:99%; MS (m/e): 398(MH⁺). 7.3.820 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926758) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toproduce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.13 (bs, 1H), 9.05 (s, 1H), 8.01 (d, 1H, J=4.2 Hz),7.76 (d, 1H, J=4.8 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.27 (dd, 1H, J=2.4 and8.1 Hz), 7.21 (dd, 1H, J=2.4 and 8.7 Hz), 7.13 (d, 1H, J=1.8 Hz), 6.95(d, 1H, J=8.1 Hz), 6.76 (d, 1H, J=8.7 Hz), 4.28 (s, 2H), 4.20 (s, 4H),2.65 (d, 3H, J=4.8 Hz), 2.15 (s, 3H); LCMS: purity: 97%; MS (m/e):440(MH⁺). 7.3.8215-Fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926759) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine and4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toproduce5-fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d ₆): δ10.09 (bs, 1H),9.96 (bs, 1H), 9.44 (bs, 1H), 8.16 (d, 1H, J=4.8 Hz), 7.81 (d, 1H, J=4.8Hz), 7.13-6.94 (m, 6H), 4.29 (s, 2H), 2.64 (d, 3H, J=4.5 Hz), 2.17 (s,3H), 2.07 (s, 3H); LCMS: purity: 99%; MS (m/e): 412(MH⁺). 7.3.8225-Fluoro-N2,N4-bis[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine (R926760) In a likemanner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N2,N4-bis[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.30 (s, 1H), 9.02 (s, 1H), 8.06 (d, 1H, J=3.6 Hz),7.94 (d, 1H, J=4.5 Hz), 7.80 (d, 1H, J=4.2 Hz), 7.58 (bs, 1H), 7.31-7.22(m, 3H), 7.05 (d, 1H, J=9.0 Hz), 6.97 (d, 1H, J=7.5 Hz), 4.41 (s, 2H),4.27 (s, 2H), 2.66 (d, 3H, J=4.2 Hz), 2.63 (d, 3H, J=4.2 Hz), 2.18 (s,3H), 2.14 (s, 3H); LCMS: purity: 100%; MS (m/e): 483(MH⁺). 7.3.8235-Fluoro-N4-(3-hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine(R926761) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,4,5-trimethoxyaniline were reacted to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.33 (s, 1H), 9.17 (s, 1H), 8.99 (s, 1H), 8.06 (d,1H, J=3.3 Hz), 7.27 (d, 1H, J=7.5 Hz), 7.08-7.02 (m, 4H), 6.46 (dd, 1H,J=1.8 and 7.8 Hz), 3.60 (s, 6H), 3.57 (s, 3H); LCMS: purity: 99%; MS(m/e): 387(MH⁺). 7.3.824N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine(R926762) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,4,5-trimethoxyaniline were reacted to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine¹H NMR (DMSO-d ₆): δ8.08 (d, 1H, J=4.8 Hz), 7.29 (d, 1H, J=2.4 Hz), 7.15(dd, 1H, J=3.0 and 9.0 Hz), 6.91 (s, 1H), 6.76 (d, 1H, J=8.7 Hz), 4.20(s, 4H), 3.61 (s, 6H), 3.59 (s, 3H); LCMS: purity: 97%; MS (m/e):429(MH⁺). 7.3.825N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-2,4-pyrimidinediamine(R926763) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,5-dichloro-4-hydroxyaniline were reacted to produceN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.50 (bs, 1H), 9.26 (bd, 2H, J=7.5 Hz), 8.06 (d, 1H,J=3.9 Hz), 7.65 (s, 2H), 7.18-7.13 (m, 2H), 6.80 (d, 1H, J=9.0 Hz), 4.20(s, 4H); LCMS: purity: 100%; MS (m/e): 424(MH⁺). 7.3.8265-Fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926890) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,5-dichloro-4-hydroxyaniline were reacted to produce5-Fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.47 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 2H), 8.09(d, 1H, J=3.6 Hz), 7.70 (s, 2H), 7.31 (dd, 1H, J=1.2 and 9.3 Hz), 7.10(t, 1H, J=7.5 Hz), 7.00 (bs, 1H), 6.48 (dd, 1H, J=1.2 and 6.9 Hz); LCMS:purity: 93%; MS (m/e): 382(MH⁺). 7.3.827N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926891) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to produceN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.85 (bs, 1H), 9.70 (bs, 1H), 8.17 (d, 1H, J=4.8Hz), 7.98 (d, 1H, J=3.9 Hz), 7.79 (d, 1H, J=2.4 Hz), 7.65 (dd, 1H, J=3.0and 9.3 Hz), 7.24-7.09 (m, 4H), 6.57 (d, 1H, J=5.7 Hz), 4.34 (s, 2H),3.82 (s, 3H), 2.62 (d, 3H, J=4.8 Hz); LCMS: purity: 95%; MS (m/e):433(MH⁺). 7.3.8285-Fluoro-N4-(3-fluoro-4-methoxyphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926892) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-fluoro-4methoxyphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethylene oxy]aniline were reacted to produce5-fluoro-N4-(3-fluoro-4-methoxyphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.68 (bs, 1H), 9.53 (bs, 1H), 8.13 (d, 1H, J=4.2Hz), 7.97 (d, 1H, J=4.8 Hz), 7.76 (dd, 1H, J=2.4 and 13.5 Hz), 7.47 (d,1H, J=7.5 Hz), 7.27-7.08 (m, 4H), 6.54 (d, 1H, J=8.4 Hz), 4.35 (s, 2H),3.80 (s, 3H), 2.63 (d, 3H, J=4.8 Hz); LCMS: purity: 94%; MS (m/e):416(MH⁺). 7.3.829N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxy-5-methylphenyl)-2,4-pyrimidinediamine(R926893) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,4-amino-m-cresol hydrogenchloride salt, and diisopropylethylamine werereacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxy-5-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.06 (s, 1H), 8.94 (s, 1H), 8.11 (s, 1H), 7.86 (d,1H, J=3.9 Hz), 7.21-7.15 (m, 2H), 7.03 (d, 1H, J=8.1 Hz), 6.59 (bd, 2H,J=8.7 Hz), 6.52 (dd, 1H, J=3.0 and 8.1 Hz), 4.17 (s, 4H), 2.05 (s, 3H);LCMS: purity: 99%; MS (m/e): 369(MH⁺). 7.3.830N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-fluoro-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926894) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-amino-5-fluorobenzotrifluoride were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-fluoro-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹HNMR (DMSO-d ₆): δ9.75 (s, 1H), 9.32 (d, 1H, J=1.2 Hz), 8.13 (d, 1H,J=3.6 Hz), 7.99 (d, 1H, J=12.3 Hz), 7.77 (s, 1H), 7.21 (d, 1H, J=2.4Hz), 7.13 (dd, 1H, J=2.1 and 8.7 Hz), 7.03 (d, 1H, J=9.0 Hz), 6.80 (d,1H, J=8.7 Hz), 4.21 (s, 4H); LCMS: purity: 97%; MS (m/e): 425(MH⁺).7.3.831N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926895) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-amino-5-methylbenzotrifluoride were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.57 (bs, 1H), 9.39 (bs, 1H), 8.12 (d, 1H, J=3.6Hz), 7.77 (s, 2H), 7.25-7.13 (m, 2H), 7.02 (s, 1H), 6.79 (d, 1H, J=9.0Hz), 4.20 (s, 4H), 2.27 (s, 3H); LCMS: purity: 100%; MS (m/e): 421(MH⁺).7.3.832N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(5-methoxy-2-methylphenyl)-2,4-pyrimidinediamine(R926896) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-methoxy-2-methylaniline were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methoxy-2-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.91 (bs, 1H), 7.61 (d, 1H, J=2.1 Hz), 7.17 (d, 1H,J=3.0 Hz), 7.05 (d, 1H, J=9.3 Hz), 7.03 (dd, 1H, J=3.0 and 8.7 Hz), 6.82(d, 1H, J=8.1 Hz), 6.68-6.60 (m, 2H), 6.55 (dd, 1H, J=2.1 and 8.1 Hz),4.26 (s, 4H), 3.70 (s, 3H), 2.22 (s, 3H); ¹⁹F NMR (282 MHz, CDCl₃):-47450; LCMS: purity: 99%; MS (m/e): 383(MH⁺). 7.3.833N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine(R926897) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and2-fluoro-5-methylaniline were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.11 (dd, 1H, J=1.8 and 8.1 Hz), 7.94 (d, 1H, J=2.7Hz), 7.08-6.84 (m, 4H), 6.74-6.67 (m, 1H), 6.64-6.59 (m, 1H), 4.27 (s,4H), 2.28 (s, 3H) ; ¹⁹F NMR (282 MHz, CDCl₃): -38659, -47267; LCMS:purity: 100%; MS (m/e): 371(MH⁺). 7.3.834N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine(R926898) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,5-difluoroaniline were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.94 (d, 1H, J=3.3 Hz), 7.20-7.11 (m, 3H), 7.02 (s,1H), 6.92-6.90 (m, 2H), 6.65 (s, 1H), 6.39 (tt, 1H, J=2.4 and 9.0 Hz),4.31 (s, 4H); ¹⁹F NMR (282 MHz, CDCl₃): -31142, -47002; LCMS: purity:97%; MS (m/e): 375(MH⁺). 7.3.835N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine(R926899) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-(trifluoromethylthio)aniline were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.73 (s, 1H), 9.47 (s, 1H), 8.13 (d, 1H, J=3.6 Hz),7.79 (d, 2H, J=9.0 Hz), 7.51 (d, 2H, J=9.0 Hz), 7.28 (d, 1H, J=2.1 Hz),7.12 (dd, 1H, J=2.4 and 9.0 Hz), 6.83 (d, 1H, J=8.7 Hz), 4.23 (s, 4H);¹⁹F NMR (282 MHz DMSO-d ₆): -12306; LCMS: purity: 97%; MS (m/e):439(MH⁺). 7.3.836N4-[3-(Benzothiazol-2-yl)-4-chlorophenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl)-2,4-pyrimidinediamine(R926900) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[3-(Benzothiazol-2-yl)-4-chlorophenyl)-2-chloro-5-fluoro-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovideN4-[3-(benzothiazol-2-yl)-4-chlorophenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.77 (s, 1H), 9.30 (s, 1H), 8.49 (d, 1H, J=3.0 Hz),8.25 (dd, 1H, J=3.0 and 9.0), 8.21-8.16 (m, 2H), 8.06 (d, 1H, J=7.8 Hz),7.92 (d, 1H, J=4.8 Hz), 7.63-7.48 (m, 3H), 7.30 (t, 1H, J=1.8 Hz), 7.22(dd, 1H, J=1.8 and 7.5 Hz), 6..95 (t, 1H, J=8.1 Hz), 6.32 (dd, 1H, J=1.2and 8.1 Hz), 4.29 (s, 2H), 2.62 (d, 1H, J=4.8 Hz); LCMS: purity: 100%;MS (m/e): 536(MH⁺). 7.3.8375-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-methoxy-4-methylphenyl)-2,4-pyrimidinediamine(R926902) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-Chloro-5-fluoro-N4-(3-methoxy-4-methylphenyl)-4-pyrimidineamine and3-methoxy-4-methylaniline were reacted to provide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-methoxy-4-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.78 (bs, 1H), 9.63 (bs, 1H), 8.15 (d, 1H, J=4.5Hz), 7.94 (d, 1H, J=4.5 Hz), 7.94 (d, 1H, J=4.5 Hz), 7.30 (dd, 1H, J=1.8and 8.4 Hz), 7.25-7.04 (m, 5H), 6.57 (d, 1H, J=8.1 Hz), 4.31 (s, 2H),3.66 (s, 3H), 2.62 (d, 1H, J=4.8 Hz), 2.09 (s, 3H); LCMS: purity: 95%;MS (m/e): 412(MH⁺). 7.3.8385-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-6-yl])-2,4-pyrimidinediamine(R926903) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and6-amino-2-(methoxycarbonyl)-(1H)-indole were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-6-yl])-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ11.53 (s, 1H), 9.37 (s, 1H), 9.18 (d, 2H, J=9.9 Hz),8.08 (d, 1H, J=3.6 Hz), 7.96 (bs, 1H), 7.46 (d, 1H, J=9.0 Hz), 7.39-7.35(m, 2H), 7.16 (t, 1H, J=2.4 Hz), 7.10-7.04 (m, 2H), 6.48 (dd, 1H, J=2.4and 7.5 Hz), 3.82 (s, 3H); LCMS: purity: 95%; MS (m/e): 394(MH⁺).7.3.8395-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926904) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoroN4-[2-(methoxycarbonyl)-(1H)-indol-6-yl])-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to provide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ9.05 (bs, 1H), 8.35 (s, 1H), 8.00 (bs, 1H), 7.66-7.62(m, 2H), 7.27-7.17 (m, 3H), 7.01-6.90 (m, 3H), 6.64 (dd, 1H, J=2.4 and8.1 Hz), 6.40 (bs, 1H). 4.49 (s, 2H), 3.94 (s, 3H), 2.75 (d, 3H, J=5.1Hz); LCMS: purity: 86%; MS (m/e): 465(MH⁺). 7.3.840N4-[3-[[4-(Ethoxycarbonyl)piperidino]methyl]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl-2,4-pyrimidinediamine(R926905) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[3-[[4-(ethoxycarbonyl)piperidino]methyl]phenyl]-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N4-[3-[[4-(ethoxycarbonyl)piperidino]methyl]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): 9.33 (s, 1H), 9.20 (s, 1H), 8.09 (d, 1H, J=4.2 Hz),7.93 (d, 1H, J=4.8 Hz), 7.82 (d, 1H, J=8.1 Hz), 7.55 (s, 1H), 7.35 (t,1H, J=2.4 Hz), 7.29-7.22 (m, 2H), 7.09 (t, 1H, J=8.1 Hz), 6.96 (d, 1H,J=7.8 Hz), 6.47 (dd, 1H, J=2.4 and 8.1 Hz), 4.32 (s, 2H), 4.02 (q, 2H,J=6.9 Hz), 3.39 (s, 2H), 2.73 (bd, 2H, J=11.1 Hz), 2.63 (d, 3H, J=4.5Hz), 2.30-2.20 (m, 1H), 1.94 (t, 2H, J=11.1 Hz), 1.74 (d, 2H, J=9.9 Hz),1.60-1.50 (m, 2H), 1.14 (t, 3H, J=6.9 Hz); LCMS: purity: 99%; MS (m/e):537(M - CH₂ ⁺). 7.3.841N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926906) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)aniline were reacted toprovideN2-[3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.91 (d, 1H, J=4.8 Hz), 7.20-7.03 (m, 6H), 6.67 (td,1H, J=2.1 and 7.5 Hz), 6.57-6.53 (m, 1H), 4.19 (q, 2H, J=6.9 Hz), 1.53(s, 6H), 1.20 (t, 3H, J=6.9 Hz); ¹⁹F NMR (282 MHz, CD₃OD): -46120; LCMS:purity: 91%; MS (m/e): 427(MH⁺). 7.3.842N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926907) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)aniline were reacted toprovideN2-[3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.92 (d, 1H, J=3.0 Hz), 7.21-7.08 (m, 4H), 7.00 (dd,1H, J=2.4 and 8.4 Hz), 6.93 (bs, 1H), 6.86 (d, 1H, J=8.7 Hz), 6.99 (d,1H, J=2.4 Hz), 6.45 (ddd, 1H, J=1.2, 1.2, and 7.8 Hz), 4.27 (s, 4H),4.23 (q, 2H, J=6.9 Hz), 1.60 (s, 6H), 1.23 (t, 3H, J=6.9 Hz); ¹⁹F NMR(282 MHz, CDCl₃): -47216; LCMS: purity: 85%; MS (m/e): 469(MH⁺). 7.3.843N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxy-4-methylphenyl)-2,4-pyrimidinediamine(R926908) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2-hydroxy-4-methylphenyl)-4-pyrimidineamine and3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)aniline were reacted toprovideN2-[3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxy-4-methylphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.86 (bs, 1H), 7.80 (bs, 1H), 7.53 (s, 1H), 7.16-6.86(m, 4H), 6.54 (d, 2H, J=7.5 Hz), 4.21 (q, 2H, J=6.9 Hz), 3.48 (s, 2H),2.20 (s, 3H), 1.60 (s, 6H), 1.22 (t, 3H, J=6.9 Hz); ¹⁹F NMR (282 MHz,CDCl₃): -46808; LCMS: purity: 96%; MS (m/e): 441(MH⁺). 7.3.844N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926909) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy)aniline were reacted toprovideN2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ9.43 (bs, 1H), 8.64 (s, 1H), 7.92 (d, 1H, J=3.6 Hz),7.66 (t, 1H, J=2.4 Hz), 7.54 (d, 1H, J=8.4 Hz), 7.44 (s, 1H), 7.19 (t,1H, J=3.0 Hz), 7.15 (d, 1H, J=8.1 Hz), 6.96 (d, 1H, J=3.0 Hz), 6.80 (dd,1H, J=1.8 and 7.5 Hz), 6.77 (dd, 1H, J=1.8 and 8.1 Hz), 6.52 (dd, 1H,J=1.8 and 7.5 Hz), 6.49-6.46 (m, 1H), 4.32 (q, 2H, J=7.2 Hz), 1.57 (s,6H), 1.31 (t, 3H, J=7.2 Hz); ¹⁹F NMR (282 MHz, CDCl₃): -47190; LCMS:purity: 93%; MS (m/e): 450(MH⁺). 7.3.8455-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine (R926913) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy)aniline were reactedto provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d ₆): δ9.35 (s, 1H), 9.20 (s, 1H),9.17 (s, 1H), 8.07 (d, 1H, J=3.3 Hz), 7.93 (d, 1H, J=3.9 Hz), 7.40-7.29(m, 3H), 7.13-7.02 (m, 3H), 6.47 (d, 1H, J=7.5 Hz), 6.33 (d, 1H, J=7.5Hz), 2.60 (s, 3H), 1.37 (s, 6H); LCMS: purity: 97%; MS (m/e): 412(MH⁺).7.3.8465-Fluoro-N4-(1,2,3,4-tetrahydroisoquin-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926914) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N4-(1,2,3,4-tetrahydroisoquin-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ7.90 (d, 1H, J=3.3 Hz), 7.47 (d, 1H, J=2.4 Hz),7.42-7.37 (m, 2H), 7.16 (t, 1H, J=8.4 Hz), 7.10-7.04 (m, 2H), 6.50 (ddd,1H, J=1.2, 2.4, and 8.1 Hz), 4.26 (s, 2H), 3.93 (s, 2H), 3.12 (t, 2H,J=6.3 Hz), 2.84-2.76 (m, 5H), ; ¹⁹F NMR (282 MHz, CD₃OD): -47489; LCMS:purity: 87%; MS (m/e): 423(MH⁺). 7.3.847N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine (R926915) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy)aniline were reactedto provide N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine. ¹H NMR (CD₃OD): δ7.26 (t, 1H, J=7.5 Hz), 7.19 (d,1H, J=9.3 Hz), 7.13 (d, 1H, J=2.4 Hz), 7.06 (dd, 1H, J=2.4 and 8.7 Hz),7.04-7.03 (m, 1H), 6.83 (d, 1H, J=9.0 Hz), 6.75 (d, 1H, J=7.2 Hz), 4.25(s, 4H), 2.76 (s, 3H), 1.43 (s, 6H); LCMS: purity: 97%; MS (m/e):454(MH⁺). 7.3.8485-Fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine (R926917) A mixture of5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (20 mg, 0.052 mmol), allylisocyanate (13mg, 0.16 mmol), and 2-(N,N-dimethylamino)pyridine (18 mg,0.15 mmol) in anhydrous THF (1 mL) were heated at 60° C. in a sealedvial for 2 days. The reaction was diluted with ethyl acetate and washedwith 1N HCl and brine. Concentration gave an oily residue which waspurified by preparative TLC (5% methanol/dichloromethane) to give theproduct5-fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]- 2,4-pyrimidinediamine. ¹H NMR (CD₃OD): δ7.93 (d, 1H, J=3.6Hz), 7.62-7.55 (m, 2H), 7.32 (s, 1H), 7.30 (t, 1H, J=8.1 Hz), 7.19-7.15(m, 2H), 6.82 (dd, 1H, J=2.4 and 8.1 Hz), 6.61 (m, 1H), 5.96-5.82 (m,1H), 5.24 (dd, 1H, J=1.8 and 16.8 Hz), 5.13 (dd, 1H, J=1.8 and 11.7 Hz),4.41 (s, 2H), 3.79 (d, 1H, J=5.4 Hz), 2.80 (s, 3H); ¹⁹F NMR (282 MHz,CD₃OD): -47357; LCMS: purity: 99%; MS (m/e): 468(MH⁺). 7.3.8495-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[3-[[(N-isopropylamino)carbonyl]-N-isopropylamino)carbonyloxy]phenyl]-2,4-pyrimidinediamine (R926916) In a like manner tothe preparation of5-fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine and isopropyl isocyanate were reacted to provide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[3-[[(N-isopropylamino)carbonyl]-N-isopropylamino)carbonyloxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.40 (bs, 1H), 9.27 (bs, 1H), 8.12 (d, 1H, J=3.6Hz), 7.94 (d, 1H, J=3.9 Hz), 7.78 (d, 1H, J=8.7 Hz), 7.64 (d, 1H, J=7.5Hz), 7.46 (s, 1H), 7.36-7.26 (m, 3H), 7.12 (t, 1H, J=8.1 Hz), 6.81-6.74(m, 1H), 6.47 (dd, 1H, J=2.4 and 8.1 Hz), 5.43 (d, 1H, J=3.9 Hz), 4.36(s, 2H), 3.65-3.55 (m, 2H), 3.14 (s, 2H), 2.63 (d, 3H, J=3.9 Hz), 1.10(d, 6H, J=7.2 Hz), 0.97 (d, 6H, J=6.6 Hz). 7.3.850N4-[3-[[N-(Ethoxycarbonylmethyl)amino]carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine (R926918) In a like manner to the preparation of5-fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]- 2,4-pyrimidinediamine and ethyl isocyanatoacetate were reactedto provideN4-[3-[[N-(ethoxycarbonylmethyl)amino]carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine. ¹H NMR (CD₃OD): δ7.94 (d, 1H, J=3.3 Hz), 7.69 (t,1H, J=1.8 Hz), 7.56 (ddd, 1H, J=1.2, 1.2, and 8.1 Hz), 7.35 (m, 1H),7.31 (t, 1H, J=8.1 Hz), 7.18 (d, 1H, J=2.4 Hz), 7.17 (d, 1H, J=1.2 Hz),6.84 (dd, 1H, J=2.4 and 8.1 Hz), 6.63-6.58 (m, 1H), 4.42 (s, 2H), 4.20(q, 2H, J=7.2 Hz), 3.93 (s, 2H), 2.80 (s, 3H), 1.27 (t, 3H, J=7.2 Hz);¹⁹F NMR (282 MHz, CD₃OD): -47371; LCMS: purity: 89%; MS (m/e): 513(MH⁺).7.3.851N4-[3-[(N-(Ethylamino)carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine (R926919) In a like manner to the preparation of5-fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine and ethyl isocyanate were reacted to provideN4-[3-[(N-(ethylamino)carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine. ¹H NMR (CD₃OD): δ7.94 (d, 1H, J=3.3 Hz),6.84-6.79 (m, 2H), 7.61-7.55 (m, 2H), 6.62-6.56 (m, 2H), 7.33-7.27 (m,1H), 7.19-7.17 (m, 1H), 4.41 (s, 2H), 3.23 (q, 2H, J=7.2 Hz), 2.80 (s,3H), 1.17 (t, 3H, J=7.2 Hz); ¹⁹F NMR (282 MHz, CD₃OD): -47378; LCMS:purity: 100%; MS (m/e): 455(MH⁺). 7.3.8525-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(4-methyl-3-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926922) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-methyl-3-trifluoromethylphenyl)-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(4-methyl-3-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.79 (bs, 1H), 9.48 (bs, 1H), 8.17 (d, 1H, J=4.2Hz), 8.10 (d, 1H, J=6.3 Hz), 7.96 (d, 1H, J=4.8 Hz), 7.89 (d, 1H, J=2.1Hz), 7.38 (d, 1H, J=9.0 Hz), 7.26-7.20 (m, 2H), 7.11 (t, 1H, J=8.4 Hz),6.53 (d, 1H, J=8.4 Hz), 4.33 (s, 2H), 2.62 (d, 3H, J=4.8 Hz), 2.39 (s,3H); LCMS: purity: 94%; MS (m/e): 450(MH⁺). 7.3.8535-Fluoro-N4-(4-fluoro-3-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926923) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-fluoro-3-methylphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to provide5-Fluoro-N4-(4-fluoro-3-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.67 (bs, 1H), 9.51 (bs, 1H), 8.14 (d, 1H, J=4.8Hz), 7.95 (d, 1H, J=4.2 Hz), 7.64 (dd, 1H, J=2.7 and 6.9 Hz), 7.57-7.50(m, 1H), 7.23-7.06 (m, 4H), 6.55 (d, 1H, J=7.5 Hz), 4.33 (s, 2H), 2.63(d, 3H, J=4.8 Hz), 2.19 (s, 3H); LCMS: purity: 94%; MS (m/e): 400(MH⁺).7.3.8545-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-trifluoromethylthiophenyl)-2,4-pyrimidinediamine(R926925) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-trifluoromethylthiophenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to provide5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-trifluoromethylthiophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.83 (bs, 1H), 9.49 (bs, 1H), 8.21-8.15 (m, 2H),8.01 (s, 1H), 7.94 (bs, 1H), 7.49 (t, 1H, J=7.8 Hz), 7.38 (d, 1H, J=7.8Hz), 7.29 (s, 1H), 7.22 (d, 1H, J=7.5 Hz), 7.14 (t, 1H, J=8.4 Hz), 6.54(d, 1H, J=9.9 Hz), 4.34 (s, 2H), 2.62 (d, 3H, J=4.8 Hz); LCMS: purity:98%; MS (m/e): 468(MH⁺). 7.3.855N2-[3,5-Bis(methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926926) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3,5-bis(methoxycarbonylmethyleneoxy)aniline were reacted to provideN2-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.92 (d, 1H, J=4.2 Hz), 7.20-7.10 (m, 3H), 6.92 (d, 2H,J=2.4 Hz), 6.52 (ddd, 1H, J=1.8, 1.8, and 7.5 Hz), 6.12 (t, 1H, J=2.4Hz), 4.55 (s, 4H), 3.77 (s, 6H); ¹⁹F NMR (282 MHz, CD₃OD): -47342; LCMS:purity: 92%; MS (m/e): 473(MH⁺). 7.3.8565-Fluoro-N2-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926927) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-hydroxy-5-(methoxycarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ8.13 (d, 1H, J=4.8 Hz), 7.37-7.33 (m, 1H), 7.11 (t,1H, J=8.4 Hz), 7.07-7.05 (m, 1H), 6.73-6.65 (m, 2H), 6.51 (dd, 1H, J=2.1and 8.1 Hz), 5.97 ((s, 1H), 4.59 (s, 2H), 3.67 (s, 3H); LCMS: purity:93%; MS (m/e): 401(MH⁺). 7.3.857N2-[3-[(N-Ethylamino)carbonyloxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926928) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-[(N-ethylamino)carbonyloxy]aniline were reacted to provideN2-[3-[(N-ethylamino)carbonyloxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.92 (d, 1H, J=3.0 Hz), 7.67-7.55 (m, 2H), 7.24 (t, 1H,J=7.5 Hz), 7.16 (t, 1H, J=7.5 Hz), 7.07-6.98 (m, 2H), 6.84-6.79 (m, 2H),6.67 (m, 2H), 6.60 (d, 1H, J=7.5 Hz), 5.22-5.14 (m, 1H), 3.36-3.27 (m,2H), 2.95 (s, 1H), 2.88 (s, 1H), 1.20 (t, 3H, J=7.5 Hz); ¹⁹F NMR (282MHz, CDCl₃): -47012; LCMS: purity: 99%; MS (m/e): 384(MH⁺). 7.3.8585-Fluoro-N2-[3-hydroxy-5-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926929) A solution of5-fluoro-N2-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(56 mg, 0.13 mmol), methylamine hydrochloride (90 mg, 1.3 mmol), anddiisopropylethylamine (0.12 mL, 0.70 mmol) in methanol (2 mL) was heatedat 100° C. for 8 h. The cooled reaction mixture was poured into 1N HCl(20 mL) saturated with NaCl, and extracted with ethyl acetate.Purification by preparative TLC (5% methanol/dichloromethane) gave theproduct,5-fluoro-N2-[3-hydroxy-5-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.29 (bs, 1H), 9.16 (s, 1H), 9.01 (s, 1H), 8.06 (d,1H, J=3.3 Hz), 7.87 (d, 1H, J=4.8 Hz), 7.42 (dd, 1H, J=1.5 and 8.1 Hz),7.13-7.05 (m, 2H), 6.89-6.81 (m, 2H), 6.45 (dd, 1H, J=2.4 and 8.4 Hz),5.92 (t, 1H, J=2.4 Hz), 4.28 (s, 2H), 3.30(bs, 1H), 2.63 (s, 3H); LCMS:purity: 94%; MS (m/e): 400(MH⁺). 7.3.859N2-[3,5-Bis[(N-methylamino)carbonylmethyleneoxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926930) In a like manner to the preparation of5-fluoro-N2-[3-hydroxy-5-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine,methylamine hydrochloride, and diisopropylethylamine were reacted togiveN2-[3,5-Bis[(N-methylamino)carbonylmethyleneoxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.91 (bs, 1H), 7.25 (t, 1H, J=1.8 Hz), 7.14-7.11 (m,1H), 6.98 (s, 1H), 6.97 (s, 1H), 6.55-6.50 (m, 1H), 6.26-6.23 (m, 1H),4.39 (s, 4H), 2.81 (s, 6H); ¹⁹F NMR (282 MHz, CD₃OD): -47307; LCMS:purity: 99%; MS (m/e): 471=(MH⁺). 7.3.8605-Fluoro-N4-[(1H)-indol-5-yl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine (R926931) In likemanner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)-indol-5-yl]-4-pyrimidineamine and3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted to provide5-fluoro-N4-[(1H)-indol-5-yl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ11.09 (bs, 1H), 9.93 (bs, 1H), 9.67 (bs, 1H), 8.12(d, 1H, J=4.81 Hz), 7.94-7.82 (m, 2H), 7.37-7.22 (m, 4H), 7.13 (bs, 1H),7.07 (t, 1H, J=8.1 Hz), 6.58 (d, 1H, J=7.8 Hz), 6.37 (s, 1H), 4.32 (s,2H), 2.61 (d, 3H, J=4.2 Hz); LCMS: purity: 92%; MS (m/e): 407(MH⁺).7.3.8615-Fluoro-N2-(3-hydroxyphenyl)-N4-[(1H)-indol-5-yl]-2,4-pyrimidinediamine(R926932) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)-indol-5-yl]-4-pyrimidineamine and3-hydroxyaniline were reacted to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[(1H)-indol-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ11.13 (s, 1H), 10.25 (bs, 1H), 9.87 (bs, 1H), 9.43(bs, 1H), 8.16 (d, 1H, J=5.1 Hz), 7.89 (d, 1H, J=0.09 Hz), 7.39-7.27 (m,3H), 7.03-6.94 (m, 2H), 6.83 (s, 1H), 6.48 (d, 1H, J=7.5 Hz), 6.40 (t,1H, J=2.1 Hz); LCMS: purity: 92%; MS (m/e): 336(MH⁺). 7.3.8625-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine(R926933) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and3-[(N-methylamino)carbonyl]aniline were reacted to provide5-fluoro-N4-[(1H)indol-6-yl]-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.99 (t, 1H, J=1.8 Hz), 7.89 (d, 1H, J=3.6 Hz),7.78-7.76 (m, 1H), 7.70 (ddd, 1H, J=1.2, 2.4, and 8.4 Hz), 7.50 (d, 1H,J=9.0 Hz), 7.31 (td, 1H, J=1.2 and 7.5 Hz), 7.23-7.17 (m, 3H), 6.43 (dd,1H, J=1.2 and 3.6 Hz), 2.73 (s, 3H); ¹⁹F NMR (282 MHz, CD₃OD): -47513;LCMS: purity: 99%; MS (m/e): 377(MH⁺). 7.3.8635-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-morpholinocarbonyl)phenyl]-2,4-pyrimidinediamine(R926934) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and3-(N-morpholinocarbonyl)aniline were reacted to provide5-fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-morpholinocarbonyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.96 (d, 1H, J=4.8 Hz), 7.73 (t, 1H, J=2.4 Hz), 7.66(d, 1H, J=1.2 Hz), 7.52 (d, 1H, J=8.1 Hz), 7.49 (ddd, 1H, J=0.09, 2.1,and 8.1 Hz), 7.33-7.26 (m, 2H), 7.19 (dd, 1H, J=1.8 and 8.7 Hz),7.12-7.06 (m, 1H), 6.45 (dd, 1H, J=1.3 and 3.0 Hz), 3.62-3.15 (m, 8H);¹⁹F NMR (282 MHz, CD₃OD): -46545; LCMS: purity: 91%; MS (m/e): 433(MH⁺).7.3.864N2-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine(R926935) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and3-[4-(ethoxycarbonyl)piperidino]aniline were reacted to provideN2-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.99 (d, 1H, J=5.1 Hz), 7.64-7.58 (m, 2H), 7.52 (d, 1H,J=8.7 Hz), 7.48 (ddd, 1H, J=1.2, 2.4, and 8.1 Hz), 7.34-7.27 (m, 2H),7.19-7.13 (m, 2H), 6.46 (dd, 1H, J=1.2 and 4.2 Hz), 4.40-4.27 (m, 1H),4.13 (q, 2H, J=6.9 Hz), 3.56-3.41 (m, 1H), 2.95-2.82 (m, 2H), 2.58-2.47(m, 1H), 1.98-1.82 (m, 1H), 1.75-7.60 (m, 1H), 1.58-1.39 (m, 2H), 1.24(t, 3H, J=6.9 Hz); ¹⁹F NMR (282 MHz, CD₃OD): -46101; LCMS: purity: 90%;MS (m/e): 503(MH⁺). 7.3.8655-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine(R926936) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-[(N-methylamino)carbonyl]aniline were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.01 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz),7.68-7.61 (m, 2H), 7.45 (t, 1H, J=8.4 Hz), 7.16-7.03 (m, 3H), 6.68 (td,1H, J=1.2 and 8.7 Hz), 2.90 (s, 3H); LCMS: purity: 95%; MS (m/e):354(MH⁺). 7.3.8665-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine(R926937) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-[(N-propylamino)carbonyl]aniline were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.00 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz),7.69-7.59 (m, 2H), 7.44 (t, 1H, J=7.5 Hz), 7.16-7.05 (m, 3H), 6.67 (td,1H, J=2.4 and 7.2 Hz), 3.34-3.29 (m, 2H), 1.65-1.56 (m, 2H), 0.96 (t,3H, J=7.5 Hz); ¹⁹F NMR (282 MHz, CD₃OD): -46049; LCMS: purity: 94%; MS(m/e): 382(MH⁺). 7.3.8675-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morphonlinocarbonyl)phenyl]-2,4-pyrimidinediamine(R926938) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-(N-morpholinocarbonyl)aniline were reacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morphonlinocarbonyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.93 (d, 1H, J=3.6 Hz), 7.84 (t, 1H, J=1.8 Hz), 7.62(ddd, 1H, J=1.2, 2.4, and 8.1 Hz), 7.32 (t, 1H, J=8.4 Hz), 7.19-7.10 (m,3H), 6.96 (dd, 1H, J=1.2 and 7.8 Hz), 6.56 (ddd, 1H, J=1.2, 3.0, and 6.9Hz), 3.78-3.34 (m, 8H); ¹⁹F NMR (282 MHz, CD₃OD): -47323; LCMS: purity:100%; MS (m/e): 410(MH⁺). 7.3.868N2-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926939) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-[[4-(ethoxycarbonyl)piperidino]carbonyl]aniline were reacted toprovideN2-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.92 (d, 1H, J=3.6 Hz), 7.82 (s, 1H), 7.62 (td, 1H,J=1.2 and 8.4 Hz), 7.30 (t, 1H, J=8.4 Hz), 7.19-7.09 (m, 3H), 6.93 (d,1H, J=7.5 Hz), 6.55 (td, 1H, J=1.2 and 7.5 Hz), 4.43 (bd, 1H, J=12.3Hz), 4.13 (q, 2H, J=6.9 Hz), 3.7 (bd, 1H, J=11.7 Hz), 3.10-2.92 (m, 2H),2.67-2.55 (m, 1H), 2.06-1.50 (m, 4H), 1.24 (t, H, J=6.9 Hz); ¹⁹F NMR(282 MHz, CD₃OD): -47299; LCMS: purity: 99%; MS (m/e): 480(MH⁺). 7.3.869N4-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926940) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamineand 3-hydroxyaniline were reacted to provideN4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.93 (d, 1H, J=3.6 Hz), 7.89 (t, 1H, J=1.8 Hz), 7.83(td, 1H, J=1.2 and 8.4 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.11-6.95 (m, 4H),6.41 (td, 1H, J=1.8 and 7.2 Hz), 4.44 (bd, 1H, J=12.9 Hz), 4.10 (q, 2H,J=7.2 Hz), 3.73 (bd, 1H, J=12.3 Hz), 3.18-2.98 (m, 2H), 2.67-2.55 (m,1H), 2.05-1.53 (m, 4H), 1.23 (t, 3H, J=7.2 Hz); ¹⁹F NMR (282 MHz,CD₃OD): -47483; LCMS: purity: 99%; MS (m/e): 480(MH⁺). 7.3.870N4-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926941) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovideN4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹HNMR (CD₃OD): δ7.95 (d, 1H, J=3.3 Hz), 7.90 (t, 1H, J=1.8 Hz), 7.80 (ddd,1H, J=0.09, 2.1, 8.1 Hz), 7.39 (t, 1H, J=7.5 Hz), 7.31 (t, 1H, J=1.2Hz), 7.17-7.06 (m, 3H), 6.60-6.54 (m, 1H), 4.48-4.38 (m, 3H), 4.10 (q,2H, J=6.9 Hz), 3.78-3.65 (m, 1H), 3.17-2.95 (m, 2H), 2.79 (s, 3H),2.65-2.53 (m, 1H), 2.01-1.52 (m, 4H), 1.22 (t, 3H, J=6.9 Hz); ¹⁹F NMR(282 MHz, CD₃OD): -47309; LCMS: purity: 99%; MS (m/e): 551(MH⁺). 7.3.871Reaction of 3-hydroxyaniline and2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamineIn like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamineand 3-hydroxyaniline were reacted to provide two products, R926942 andR926943. 7.3.872N4-(1-Ethoxy-1,2,3,4-tetrahydronaphthalen-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926942) ¹H NMR (DMSO-d ₆): δ9.23 (bs, 1H), 9.14 (bs, 1H), 8.97 (bs,1H), 8.04 (d, 1H, J=3.6 Hz), 7.71 (dd, 1H, J=2.4 and 7.5 Hz), 7.56 (bs,1H), 7.14-6.98 (m, 3H), 6.93 (t, 1H, J=8.1 Hz), 6.29 (bd, 1H, J=7.2 Hz),4.35 (bs, 1H), 3.59-3.36 (m, 2H), 2.69-2.60 (m, 2H), 1.89-1.78 (m, 2H),1.72-1.56 (m, 2H), 1.08 (t, 3H, J=6.9 Hz); LCMS: purity: 96%; MS (m/e):395(MH⁺). 7.3.8735-Fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926943) ¹H NMR (DMSO-d ₆): δ9.19 (bs, 2H), 9.01 (s, 1H), 8.04 (d, 1H,J=3.6 Hz), 7.56-7.46 (m, 2H), 7.16-7.03 (m, 3H), 6.94 (t, 1H, J=8.1 Hz),6.46 (d, 1H, J=9.6 Hz), 6.03 (dd, 1H, J=1.8 and 8.1 Hz), 6.09-6.01 (m,1H), 2.69 (t, 2H, J=8.4 Hz), 2.28-2.20 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): -46541; LCMS: purity: 98%; MS (m/e): 349(MH⁺). 7.3.8745-Fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926944) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ8.07 (d, 1H, J=3.9 Hz), 7.53-7.45 (m, 2H), 7.32-7.29(m, 2H), 7.11-7.01 (m, 2H), 6.49-6.40 (m, 2H), 6.08-6.00 (m, 1H), 4.32(s, 2H), 2.69 (t, 2H, J=8.4 Hz), 2.62 (s, 3H); LCMS: purity: 99%; MS(m/e): 420(MH⁺). 7.3.875N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926945) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and3-hydroxyaniline were reacted to produceN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.91 (d, 1H, J=5.4 Hz), 7.71 (d, 1H, J=2.4 Hz), 7.58(dd, 1H, J=3.0 and 9.0 Hz), 7.15 (t, 1H, J=8.4 Hz), 7.06 (d, 1H, J=8.7Hz), 6.92 (td, 1H, J=1.8 and 9.9 Hz), 6.88 (t, 1H, J=1.8 Hz), 6.61 (ddd,1H, J=1.2, 2.4, and 8.1 Hz), 3.89 (s, 3H), ; ¹⁹F NMR (282 MHz, CD₃OD):-46612; LCMS: purity: 98%; MS (m/e): 362(MH⁺). 7.3.876N2,N4-Bis(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926946) In a like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-methoxyaniline werereacted to provideN2,N4-Bis(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d ₆): δ9.90 (bs, 1H), 9.68 (bs, 1H), 8.16 (d, 1H, J=4.8 Hz),7.72 (d, 1H, J=2.4 Hz), 7.65 (d, 1H, J=2.1 Hz), 7.58 (dd, 1H, J=2.4 and9.0 Hz), 7.38 (dd, 1H, J=2.7 and 9.3 Hz), 7.12 (d, 1H, J=8.7 Hz), 7.12(d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=8.7 Hz), 3.83 (s, 3H), 3.79 (s, 3H);LCMS: purity: 99%; MS (m/e): 410(MH⁺). 7.3.8775-Fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926947) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxo-naphthalen-7-yl)-4-pyrimidineamineand 3-[(N-methylamino)carbonylmethyleneoxy]aniline were reacted toprovide5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxo-naphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d ₆): δ9.89 (bs, 1H),9.55 (bs, 1H), 8.17 (d, 1H, J=4.2 Hz), 8.04-7.93 (m, 3H), 7.32 (d, 1H,J=8.7 Hz), 7.25-7.16 (m, 2H), 7.09 (t, 1H, J=7.5 Hz), 6.52 (dd, 1H,J=2.4 and 8.1 Hz), 4.28 (s, 2H), 2.90 (t, 2H, J=6.0 Hz), 2.63 (d, 3H,J=4.8 Hz), 2.59 (t, 2H, J=6.6 Hz), 2.02 (t, 2H, J=6.6 Hz); LCMS: purity:93%; MS (m/e): 436(MH⁺). 7.3.8785-Fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxyiminonaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926948) A solution of5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxo-naphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(42 mg, 0.095 mmole) and hydroxylamine hydrochloride (8.5 mg, 0.12mmole) in DMF (1 mL)was heated at 60° C. for 12 h. The reaction mixturewas cooled to rt and then poured into brine (20 mL). A brown solid wascollected by suction filtration and further purified by reverse phasechromatography to provide5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxyiminonaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ8.13-8.05 (m, 2H), 7.99-7.92 (m, 2H), 7.77-7.72 (m,1H), 7.33-7.21 (m, 2H), 7.14 (d, 1H, J=8.7 Hz), 7.10-7.02 (m, 1H), 6.47(dd, 1H, J=2.4 and 7.5 Hz), 4.30 (s, 2H), 2.90 (t, 1H, J=6.0 Hz),2.70-2.40 (m, 6H), 2.07-1.98 (m, 1H), 1.74 (t, 1H, J=6.6 Hz); LCMS:purity: 96%; MS (m/e): 451(MH⁺). 7.3.8795-Fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926949) To a 0° C. suspension of5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxo-naphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(50mg, 0.11 mmol) in anhydrous THF (2.0 mL) was added lithiumborohydride(5 mg, 0.23 mmole). The reaction mixture was warmed to rt, stirred for 8h, and then quenched with methanol. The reaction mixture was poured intowater and then extracted with ethyl acetate. Purification by preparativeTLC (5% methanol/dichloromethane) provided5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine.LCMS: purity: 96%; MS (m/e): 438(MH⁺). 7.3.880N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine (R926950) In a like manner to thepreparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-2-(methoxycarbonyl)benzofuran were reacted to produceN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.34 (bs, 2H), 8.10-8.07 (m, 2H), 7.78 (t, 1H, J=2.7Hz), 7.66-7.53 (m, 4H), 7.12 (d, 1H, J=9.3 Hz), 3.87 (s, 3H), 3.85 (s,3H); LCMS: purity: 99%; MS (m/e): 443(MH⁺). 7.3.881N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine (R926951) In alike manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted toproduce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ10.31 (bs, 1H), 10.04 (bs, 1H), 8.21 (d, 1H, J=4.8 Hz), 7.75 (t,1H, J=3.0 Hz), 7.54 (td, 1H, J=3.0 and 9.0 Hz), 7.34 (s, 1H), 7.20-7.15(m, 2H), 6.80 (d, 1H, J=8.1 Hz), 5.38-5.31 (m, 1H), 3.85 (s, 3H), 3.69(s, 3H), 3.49 (dd, 1H, J=11.1 and 16.5 Hz); LCMS: purity: 99%; MS (m/e):446(MH⁺). 7.3.882N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine(R926953) In a like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamineand 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted toproduceN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.99 (bs, 1H), 9.49 (bs, 1H), 8.18 (d, 1H, J=4.5Hz), 8.08 (t, 1H, J=2.4 Hz), 7.81-7.74 (m, 1H), 7.49 (d, 1H, J=8.1 Hz),7.42 (s, 1H), 7.20 (d, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.7 Hz), 5.36 (m,1H), 3.80-3.47 (m, 4H), 3.20 (dd, 1H, J=6.0 and 16.5 Hz); LCMS: purity:100%; MS (m/e): 500(MH⁺). 7.3.883N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine(R926954) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine,methylamine hydrogen chloride salt, and diisopropylethylamine werereacted to provideN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.59 (s, 1H), 9.10 (s, 2H), 8.13-8.10 (m, 1H),8.08-7.98 (m, 1H), 7.82 (d, 1H, J=8.1 Hz), 7.48-7.42 (m, 2H), 7.24 (d,1H, J=8.7 Hz), 6.72 (d, 1H, J=8.7 Hz), 5.06 (dd, 1H, J=5.4 and 9.3 Hz),3.39 (dd, 1H, J=10.5 and 15.6 Hz), 3.15 (dd, 1H, J=6.3 and 15.9 Hz),2.59 (d, 3H, J=4.5 Hz); LCMS: purity: 95%; MS (m/e): 499(MH⁺). 7.3.884N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine(R926955) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine,methylamine hydrochloride, and diisopropylethylamine were reacted toprovideN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.24 (s, 1H), 8.99 (s, 2H), 8.02 (d, 1H, J=3.0 Hz),7.80-7.75 (m, 1H), 7.63 (d, 1H, J=9.0 Hz), 7.47 (s, 1H), 7.23 (d, 1H,J=8.1 Hz), 7.07 (d, 1H, J=8.7 Hz), 6.69 (d, 1H, J=8.1 Hz), 5.05 (dd, 1H,J=2.1 and 9.9 Hz), 3.37 (dd, 1H, J=10.5 and 15.9 Hz), 3.13 (dd, 1H,J=6.0 and 15.9 Hz), 2.59 (d, 3H, J=4.5 Hz); LCMS: purity: 95%; MS (m/e):445(MH⁺). 7.3.8855-Fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R926956) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine, methylaminehydrochloride, and diisopropylethylamine were reacted to provide5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.11 (s, 1H), 8.92 (s, 1H), 8.06-7.98 (m, 1H), 7.97(d, 1H, J=4.2 Hz), 7.60-7.52 (m, 3H), 7.20 (d, 1H, J=8.1 Hz), 6.85 (d,2H, J=8.7 Hz), 6.67 (d, 1H, J=9.0 Hz), 5.04 (dd, 1H, J=5.7 and 9.9 Hz),4.56 (quintet, 1H, J=6.6 Hz), 3.36 (dd, 1H, J=10.5 and 16.5 Hz), 3.10(dd, 1H, J=5.7 and 15.3 Hz), 2.59 (d, 1H, J=4.5 Hz), 1.24 (d, 6H, J=6.6Hz); LCMS: purity: 96%; MS (m/e): 438(MH⁺). 7.3.886N2,N4-Bis(3-phenylphenyl)-2,4-pyrimidinediamine (R925809) In a likemanner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-aminobiphenyl were reacted toprovide N2,N4-Bis(3-phenylphenyl)-2,4-pyrimidinediamine. LCMS: purity:98%; MS (m/e): 415(MH⁺). 7.3.887 2-Dimethylamine-5-fluoro-N4-(thyrosinylmethyl ester) pyrimidine (R940110) A solution of2,4-dichloro-5-fluoropyrimidine (0 .03 g, 0.18 mmol) and L-tyrosinemethyl ester (0.14 g, 0.7 mmol) in DMF was heated at 100° C. for 3 days.The reaction mixture was cool to room temperature and diluted with H₂O(10 mL). Upon saturation with sodium chloride it was extracted withethyl acetate (3 × 15 mL), dried over anhydrous sodium sulfate and thesolvent was removed. The resulting residue was filtered through a pad ofsilica gel (200-400 mesh, hexanes/EtOAc 2/8) to obtain2-dimethylamine-5-fluoro-N4-(thyrosinyl methyl ester) pyrimidineR940110. ¹H NMR (CDCl₃): δ7.76 (1H, d, J=3.2 Hz), 7.00 (2H, d, J=7.5Hz), 6.76 (2H, d, J=7.5 Hz), 5.20 (1H, d, J=7.5 Hz), 4.90 (1H, q, J=5.0Hz), 3.71 (3H, s), 3.14 (2H, m), 3.08 (6H, s) ; purity: 98% ; MS (m/e) :335 (M+H). 7.3.8885-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine(R940299) To a solution of2-chloro-5-fluoro-N4-(3-aminocarbonylphenyl)-4-pyrimidineamine (0.050 g,0.18 mmol) in (2 mL) was added3-(methylaminocarbonylmethyleneoxy)aniline (0.1 g, 0.5 mmol). Themixture was heated in a sealed tube at 100° C. for 24 h. The resultingreaction was diluted with H₂O (10 mL), acidified with 2N HCl (pH >2),saturated with sodium chloride and the resulting solid was filtered togive the desired product5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamineR940299. Purification can be done by filtration through a pad of silicagel using 1-5% MeOH in CH₂Cl₂ or by crystallization using an appropriatesolvent system. Alternatively, the reaction of equimolar amount of2-chloro-5-fluoro-N4-(3-aminocarbonylphenyl)-4-pyrimidineamine and3-(methylaminocarbonylmethyleneoxy) aniline in MeOH in a pressure tubeat 110° C. for 24 h or, in EtOH using microwave at 175° C. for 30-60 minfollowed by aqueous work up, also gave the desired product. ¹H NMR(DMSO-d₆): δ9.79 (1H, s), 9.49 (1H, s), 8.26 (1H, d, J=3.9 Hz), 8.15(1H, t, J=1.8 Hz), 8.10-8.02 (3H, m), 7.68 (1H, d, J=7.5 Hz), 7.51 (1H,t, J=7.9 Hz), 7.48 (1H, s), 7.38 (2H, m), 7.20 (1H, t, J=8.4 Hz), 6.60(1H, d, J=9.3 Hz), 4.45 (2H, s), 2.74 (3H, d, J=4.8 Hz) ; purity: 95 % ;MS (m/e): 411 (MH+). 7.3.8895-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine(R940300) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamineR940300.¹H NMR (DMSO-d₆): δ9.66 (1H, s), 9.45 (1H, s), 8.21 (1H, d, J=3.9 Hz),8.06 (2H, m), 8.01 (1H, t, J=2.7 Hz), 7.35 (2H, m), 7.23 (1H, d, J=9Hz),7.18 (1H, t, J=8.1 Hz), 6.60 (1H, d, J=7.8 Hz), 4.45 (2H, s), 3.91 (3H,s), 3.84 (3H, s), 2.74 (3H, d, J=3.6 Hz) ; purity: 93% ; MS (m/e): 456(MH+). 7.3.8905-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine(R940301) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and3-methyloxycarbonyl-4-methoxyaniline were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamineR940301. ¹H NMR (DMSO-d₆): δ9.93 (1H, s), 9.79 (1H, s), 9.54 (1H, s),8.26 (1H, s, J=4.5 Hz), 7.92 (1H, s), 7.81 (1H, dd, J=9.3 Hz, J=2.7 Hz),7.32 (1H, d, J=8.1 Hz), 7.20-7.13 (3H, m), 6.64 (1H, d, J=8.1 Hz), 3.89(3H, s), 3.84 (3H, s) ; purity: 97% ; MS (m/e): 385 (MH+). 7.3.8915-Fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine(R940304) A mixture of2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine(0.15 g, 0.4 mmol), methylamine hydrochloride (0.324 g, 48 mmol) anddiisopropylethylamine (0.84 mL, 48 mmol) in MeOH (2 mL) was heated in asealed tube at 100° C. for 24 h (followed by TLC). The reaction wascooled to room temperature and diluted with H₂O (20 mL). The solid wasfiltered, washed with H₂O and dried to obtain5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamineR940304. ¹H NMR (DMSO-d₆): δ10.65 (1H, s), 8.48 (1H, s), 8.29 (2H, m),7.93 (1H, m), 7.28 (1H, d, J=9 Hz), 4.00 (3H, s), 2.94 (3H, s), 2.90(3H, d, J=4.5 Hz) ; purity: 90% ; MS (m/e): 306 (MH+); 7.3.8925-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine(R940306) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamineR940306.¹H NMR (DMSO-d₆): δ9.28 (1H, s), 9.21 (1H, s), 8.12 (1H, d, J=3.9 Hz),8.06 (1H, d, J=2.7 Hz), 7.99 (1H, m), 7.89 (1H, dd, J=9.3 Hz, J=2.7 Hz),7.52 (1H, q, J=4.9 Hz), 7.41 (1H, t, J=2.1 Hz), 7.37 (1H, d, J=7.5 Hz),7.10 (1H, t, J=8.1 Hz), 6.83 (1H, d, J=9 Hz), 6.53 (1H, dd, J=8.1 Hz,J=1.8 Hz), 4.40 (2H, s), 3.82 (3H, s), 2.96 (3H, d, J=5.1 Hz), 2.73 (3H,d, J=4.5 Hz) ; purity: 93% ; MS (m/e): 455 (MH+). 7.3.893(R)-N2-[3-(dihydroxypropylaminocarbonylmethyleneoxy)-phenyl]-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine(R940307) In like manner to the preparation of5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine,5-fluoro-N4-(3-isopropylphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand (R)-3-amino-1,2-propanediol were reacted to give(R)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamineR940307. ¹H NMR (DMSO-d₆): δ9.96 (1H, s), 9.80 (1H, s), 8.29 (1H. d,J=4.5 Hz), 7.98 (1H, t, J=5.5 Hz), 7.77 (1H, d, J=7.2 Hz), 7.57 (1H, s),7.37 (1H, t, J=7.8 Hz), 7.30-7.22 (3H, m), 7.12 (1H, d, J=7.8 Hz), 6.70(1H, d, J=7.5 Hz), 4.47 (2H, s), 3.62 (1H, m), 3.38 (3H, m), 3.15 (1H,m), 2.94 (1H, quint, J=6.9 Hz), 1.27 (6H, d, 6.9 Hz) ; purity: 99%; MS(m/e): 469 (M), 470 (MH+). 7.3.894N4-(3-tert-Butylpheny)-5-fluoro-N2-[3-(1,1-dimethyl-2-hydroxyethylaminocarbonylmethyleneoxy)-phenyl]-2,4-pyrimidinediamine(R940308) In like manner to the preparation of5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine,N4-(3-tert-butylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand 2-amino-2-methyl-1-propanol were reacted to giveN4-(3-tert-butylpheny)-5-fluoro-N2-[3-(1,1-dimethyl-2-hydroxyethylaminocarbonylmethyleneoxy)-phenyl]-2,4-pyrimidinediamineR940308. ¹H NMR (DMSO-d₆): δ9.38 (1H, s), 9.28 (1H, s), 8.20 (1H, d,J=3.9 Hz), 7.99 (1H, d, J=7.5 Hz), 7.60 (1H, t, J=2.1 Hz), 7.46 (1H, s),7.37 (2H, t, J=7.9 Hz), 7.30 (1H, s), 7.19 (2H, t, J=7.9 Hz), 6.56 (1H,dd, J=7.5 Hz, J=1.5 Hz), 5.06 (1H, t, J=5.7 Hz), 4.37 (2H, s), 3.40 (2H,m), 1.36 (9H, s), 1.32 (6H, s) ; purity: 93% ; MS (m/e): 482 (MH+).7.3.895N4-(3-Aminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940309) A mixture ofN4-[3-(N-tert-butoxycarbonyl-N-aminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline in MeOH was heated in asealed tube at 100° C. for 12 h. The reaction was cool to roomtemperature and the solvent was removed under reduce pressure. Theresulting residue was filtered through a pad of silica gel (200-400mesh, EtOAc/MeOH (2M NH₃) 95:5) to obtain the desired productN4-(3-aminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940309. ¹H NMR (DMSO-d₆): δ9.41 (1H, s), 9.23 (1H, s), 8.20 (1H, d,J=3.9 Hz), 8.00 (1H, m), 7.78 (1H, s), 7.72 (1H, d, J=7.2 Hz), 7.46 (1H,s), 7.42-7.33 (2H, m), 7.21 (1H, t, J=7.8 Hz), 7.14 (1H, d, J=7.8 Hz),6.59 (1H, dd, J=8.1 Hz, J=2.4 Hz), 4.42 (2H, s), 3.79 (2H, s), 2.74 (3H,d, J=4.8 Hz) ; purity: 98% ; MS (m/e): 397 (MH+). 7.3.896 N4-[3-(2-(N4-(3-aminomethylenephenyl)-5-fluoro-4-pyrimidineamine)-N-methylaminomethylene)-phenyl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidineamine(R940311) A mixture ofN4-[3-(N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(0.05 g, 0.18 mmol) and 3-(methylaminocarbonylmethyleneoxy)aniline (0.04g, 0.22 mmol) in EtOH (0.5 mL),was heated at 175° C. for 35 min usingmicrowave. An aqueous work up gave the desired N4-[3-(2-(N4-(3-aminomethylenephenyl)-5-fluoro-4-pyrimidineamine)-N-methylaminomethylene)-phenyl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidineamineR940311. ¹H NMR (DMSO-d₆): δ9.48 (1H, s), 9.31 (1H, s), 9.26 (1H, s),8.20 (1H, d, J=3.6 Hz), 8.10-8.05 (4H, m), 7.62 (1H, s), 7.49 (2H, m),7.41 (1H, t, J=8.1 Hz), 7.36 (2H, m), 7.22 (1H, t, J=8.4 Hz), 7.17 (1H,t, J=8.4 Hz), 7.06 (1H, d, J=7.5 Hz), 6.59 (1H, dd, J=8.4 Hz, J=2.4 Hz),6.54 (1H, dd, J=7.8 Hz, J=2.4 Hz), 4.93 (2H, s), 4.46 (2H, s), 4.45 (2H,s), 3.28 (3H, d, J=3Hz), 2.73 (6H, m) ; purity: 98%; MS (m/e) : 684 (M),685 (MH+). 7.3.8975-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-iso-propylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine(R940312) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(3-N-iso-propylaminomethylene-4-methoxyphenyl)-4-pyrimidineamine and3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-iso-propylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamineR940312.¹H NMR (DMSO-d₆): δ10.09 (1H, s), 9.88 (1H, s), 8.25 (1H, d, J=4.8 Hz),8.07 (1H, d, J=2.7 Hz), 8.05 (1H, m), 7.81 (1H, dd, J=9 Hz, J=2.7 Hz),7.63 (1H, s), 7.25 (2H, m), 7.17 (1H, t, J=8.25 Hz), 6.91 (1H, d, J=9Hz), 6.68 (1H, d, J=8.1 Hz), 4.42 (2H, s), 3.85 (1H, m), 3.81 (3H, s),2.72 (3H, d, J=4.2 Hz), 1.30 (6H, d, J=6 Hz) ; purity: 97% ; MS (m/e):483 (MH+). 7.3.8985-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamine(R940314) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produce5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamineR940314.¹H NMR (DMSO-d₆): δ9.33 (1H, s), 9.21 (1H, s), 8.15 (1H, d, J=3.6 Hz),8.04 (1H, d, J=4.8 Hz), 7.82 (1H, dd, J=9 Hz, J=2.7 Hz), 7.57 (1H, d,J=3 Hz), 7.47 (1H, t, J=1.95 Hz), 7.34 (1H, m), 7.18 (1H, t, J=8.1 Hz),7.04 (1H, d, J=9 Hz), 6.56 (1H, dd, J=8.4 Hz, J=2.1 Hz), 4.40 (2H, s),3.86 (3H, s), 3.63 (4H, t, J=4.5 Hz), 3.53 (2H, s), 2.74 (3H, d, J=4.5Hz), 2.46 (4H, m) ; purity: 97%; MS (m/e): 497 (MH+). 7.3.899N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamine(R940316) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-4-pyrimidineamineand 4-amino-2-chloro-6-methylphenol were reacted to produceN2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamineR940316. ¹H NMR (DMSO-d₆): δ9.28 (1H, s), 9.01 (1H, s), 8.65 (1H, s),8.11 (1H, d, J=3.9 Hz), 7.76 (1H, dd, J=9 Hz, J=3 Hz), 7.61 (1H, d,J=2.4 Hz), 7.50 (1H, d, J=2.7 Hz), 7.30 (1H, d, J=2.1 Hz), 7.04 (1H, d,J=8.7 Hz), 3.87 (3H, s), 3.63 (4H, t, J=4.3 Hz), 3.52 (2H, s), 2.45 (4H,m), 2.17 (3H, s) ; purity: 97% ; MS (m/e): 474 (MH+). 7.3.900N4-(3-N-methylaminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940317) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N4-[3-(N-tert-butoxycarbonyl-N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-(3-N-methylaminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940317. ¹H NMR (DMSO-d₆): δ9.41 (1H, s), 9.31 (1H, s), 9.29 (1H, s),8.20 (1H, d, J=3 Hz), 8.05 (1H, m), 7.80 (1H, d, J=7.8 Hz), 7.74 (1H,s), 7.45-7.35 (3H, m), 7.21 (1H, t, J=8.1 Hz), 7.13 (1H, d, J=7.5 Hz),6.59 (1H, d, J=9.6 Hz), 4.43 (2H, s), 3.71 (2H, s), 2.75 (3H, d, J=4.2Hz), 2.35 (3H, s) ; purity: 83.9% ; MS (m/e): 411 (MH+). 7.3.901N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-piperazinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamine(R940318) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N4-[3-(N-piperazinomethylene)-4-methoxyphenyl]-2-chloro-5-fluoro-4-pyrimidineamineand 4-amino-2-chloro-6-methylphenol were reacted to produceN2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-piperazinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamineR940318.¹H NMR (DMSO-d₆): δ9.27 (1H, s), 9.00 (1H, s), 8.10 (1H, d, J=3.6 Hz),7.75 (1H, dd, J=8.7 Hz, J=2.7 Hz), 7.61 (1H, d, J=2.4 Hz), 7.49 (1H, d,J=2.4 Hz), 7.31 (1H, d, J=2.4 Hz), 7.03 (1H, d, J=9 Hz), 3.86 (3H, s),3.49 (2H, s), 2.75 (4H, t, J=4.65 Hz), 2.39 (4H, m), 2.17 (3H, s) ;purity: 95%; MS (m/e): 473 (MH+). 7.3.902N4-(3-(N-tert-Butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine (R940319) In like manner tothe preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,N4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940319.¹H NMR (DMSO-d₆): δ9.44 (1H, s), 8.95 (1H, s), 8.15 (1H, d, J=3.6 Hz),8.06 (1H, m), 7.83 (1H, m), 7.74 (1H, m), 7.56 (1H, m), 7.37 (1H, m),7.20 (1H, t, J=7.9 Hz), 7.02 (1H, d, J=9.3 Hz), 6.57 (1H, d, J=7.8 Hz),4.44 (2H, s), 4.42 (1H, m), 4.33 (2H, s), 3.89 (3H, s), 2.74 (3H, d,J=4.8 Hz), 1.52-1.30 (9H, m), 1.16 (6H, d, J=6.9 Hz) ; purity: 98% ; MS(m/e): 569 (MH+). 7.3.903N4-(3-N,N-Dimethylaminomethylene-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940321) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(3-N,N-dimethylaminomethylene-4-methoxyphenyl)-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-(3-N,N-dimethylaminomethylene-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940321. ¹H NMR (DMSO-d₆): δ9.32 (1H, s), 9.23 (1H, s), 8.14 (1H, d,J=3.9 Hz), 8.05 (1H, m), 7.83 (1H, dd, J=8.7 Hz, J=2.4 Hz), 7.55 (1H, d,J=2.4 Hz), 7.45 (1H, s), 7.36 (1H, d, J=8.4 Hz), 7.18 (1H, t, J=8.1 Hz),7.03 (1H, d, J=9 Hz), 6.56 (1H, dd, J=7.2 Hz, J=1.5 Hz), 4.41 (2H, s),3.86 (3H, s), 2.73 (3H, d, J=4.5 Hz), 2.24 (6H, s) ; purity: 91.8% ; MS(m/e): 455 (MH+). 7.3.904N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940323) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940323. ¹H NMR (DMSO-d₆): δ10.70 (1H, s), 9.45 (1H, s), 9.19 (1H, s),8.17 (1H, d, J=3.9 Hz), 8.05 (1H, m), 7.43-7.34 (4H, m), 7.17 (1H, t,J=8.25 Hz), 6.98 (1H, d, J=8.4 Hz), 6.56 (1H, dd, J=7.8 Hz, J=2.1 Hz),4.25 (2H, s), 2.74 (3H, d, J=4.5 Hz), 1.5 (6H, s) ; purity: 98.7% ; MS(m/e): 467 (MH+). 7.3.905N4-[3-Dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940337) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940337. ¹H NMR (DMSO-d₆): δ9.28 (1H, s), 9.20 (1H, s), 8.34 (1H, dd,J=4.8 Hz, J=1.2 Hz), 8.14 (1H, d, J=3.8 Hz), 8.03 (1H, m), 7.64-7.60(2H, m), 7.51-7.46 (3H, m), 7.37 (1H, d, J=8.4 Hz), 7.17 (1H, t, J=8.1Hz), 6.94-6.91 (2H, m), 6.55 (1H, dd, J=8.4 Hz, J=3Hz), 4.42 (2H, s),3.93 (2H, s), 2.74 (3H, d, J=4.5 Hz), 1.32 (6H, s) ; purity: 98.2% ; MS(m/e): 530 (MH+); 7.3.906N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine(R940338) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 5-amino-1-methyl-1-indazole were reacted to produceN4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamineR940338. ¹H NMR (DMSO-d₆): δ10.73 (1H, s), 9.39 (1H, s), 9.17 (1H, s),8.21 (1H, s), 8.16 (1H, d, J=3.9 Hz), 7.87 (1H. s), 7.56 (2H, m), 7.41(1H, m), 7.32 (1H, s), 7.00 (1H, d, J=8.4 Hz), 4.07 (3H, s), 1.51 (6H,s) ; purity: 99.2% ; MS (m/e): 434 (MH+). 7.3.907N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R921303) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR921303.¹H NMR (DMSO-d₆): δ12.05 (1H, s), 9.67 (1H, s), 9.27 (1H, s), 8.24 (1H,d, J=3.6 Hz), 8.05 (1H, m), 7.73-7.68 (1H, m), 7.56 (1H, t, J=2.7 Hz),7.50 (1H, s), 7.36 (2H, d, J=8.7 Hz), 7.19 (1H, t, J=8.2 Hz), 6.58 (1H,dd, J=8.4 Hz, J=2.4 Hz), 4.34 (2H, s), 2.74 (3H, d, J=4.5 Hz); ¹⁹F NMR(DMSO-d₆): δ-21643, -46385 ; purity: 100% ; MS (m/e): 475 (MH+). 7.3.908N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940345) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940345.¹H NMR (DMSO-d₆): δ11.23 (1H, s), 9.69 (1H, s), 9.54 (1H, s), 8.50 (1H,s), 8.25 (1H, d, J=3.3 Hz), 8.06 (1H, m), 7.96 (1H, t, J=2.5 Hz),7.41-7.36 (2H, m), 7.24 (1H, t, J=8.25 Hz), 6.34 (1H, d, J=8.7 Hz), 4.47(2H, s), 2.74 (3H, d, J=3.3 Hz), 1.53 (6H, s) ; purity: 98.4% ; MS(m/e): 468 (MH+). 7.3.909N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940346) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to produceN4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineR940346.¹H NMR (DMSO-d₆): δ10.75 (1H, s), 8.25 (1H, d, J=4.5 Hz), 7.42-7.37 (1H,m), 7.34 (1H, s), 7.10 (3H, m), 7.00 (1H, d, J=8.4 Hz), 6.53 (1H, m),1.50 (6H, s) ; purity: 97.5% ; MS (m/e): 396 (MH+). 7.3.910N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R940347) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-(methylaminocarbonylmethyleneoxy)aniline were reacted to produceN4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineR940347.¹H NMR (DMSO-d₆): δ11.20 (1H, s), 9.46 (1H, s), 8.26 (1H, d, J=3.6 Hz),8.06 (1H, s), 7.71 (1H, m), 7.49 (1H, d, J=8.4 Hz), 7.45 (1H, s), 7.38(1H, d, J=9 Hz), 7.21 (1H, t, J=8.1 Hz), 6.61 (1H, d, J=8.7 Hz), 4.47(2H, s), 2.74 (3H, s), 1.52 (6H, s); purity: 100% ; MS (m/e): 468 (MH+).7.3.911N4-[3-Dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940348) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to produceN4-[3-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineR940348. ¹H NMR (DMSO-d₆): δ9.25 (1H, s), 9.23 (1H, s), 9.02 (1H, s),8.34 (1H, d, J=4.5 Hz), 8.11 (1H, d, J=3.3 Hz), 7.62 (2H, m), 7.52 (2H,m), 7.22 (1H, s), 7.19 (1H, d, J=7.5 Hz), 7.03 (1H, t, J=7.9 Hz), 6.93(2H, m), 6.38 (1H, d, J=7.8 Hz), 3.93 (2H, s), 1.32 (6H, s) ; purity:96.5%. 7.3.912N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R940349) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to produceN4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineR940349. ¹H NMR (DMSO-d₆): δ12.03 (1H, s), 9.63 (1H, s), 9.26 (1H, s),9.09 (1H, s), 8.21 (1H, d, J=3.6 Hz), 7.70 (1H, dd, J=9 Hz, J=2.4 Hz),7.59 (1H, d, J=2.7 Hz), 7.34 (1H, d, J=9.3 Hz), 7.26 (1H, s), 7.16 (1H,d, J=7.8 Hz), 7.04 (1H, t, J=8.2 Hz), 6.41 (1H, d, J=10.2 Hz) ; ¹⁹F NMR(DMSO-d₆): δ-21646, -46516 ; purity: 95.8% ; MS (m/e): 404 (MH+);7.3.913N2,N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine(R940350) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-5-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 6-amino-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one were reacted toproduceN2,N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamineR940350. ¹H NMR (DMSO-d₆): δ10.68 (1H, s), 10.62 (1H, s), 9.38 (1H, s),9.04 (1H, s), 8.11 (1H, d, J=3.6 Hz), 7.46 (1H, dd, J=8.1 Hz, J=1.8 Hz),7.33-7.26 (3H, m), 6.95 (1H, d, J=8.7 Hz), 6.84 (1H, d, J=8.4 Hz), 1.49(6H, s), 1.45 (6H, s) ; purity: 95.4% ; MS (m/e): 479 (MH+). 7.3.914N2-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine(R940351) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one were reacted toproduceN2-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamineR940351. ¹H NMR (DMSO-d₆): δ11.99 (1H, s), 10.74 (1H, s), 9.64 (1H, s),9.50 (1H, s), 8.19 (1H, d, J=3.9 Hz), 7.50 (2H, m), 7.43 (1H, dd, J=8.4Hz, J=1.8 Hz), 7.32 (1H, s), 7.20 (1H, d, J=9.3 Hz), 6.98 (1H, d, J=8.7Hz), 1.49 (6H, s) ; purity: 94.77% ; MS (m/e): 487 (MH+). 7.3.915N2,N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine(R940352) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one were reacted toproduceN2,N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamineR940352. ¹H NMR (DMSO-d₆): δ12.08 (1H, s), 12.00 (1H, s), 9.72 (1H, s),9.44 (1H, s), 8.23 (1H, d, J=3.6 Hz), 7.73 (1H, dd, J=11.1 Hz, J=1.5Hz), 7.6 (1H, s), 7.56 (1H, s), 7.51 (1H, dd, J=9.6 Hz, J=2.4 Hz), 7.35(1H, d, J=9 Hz), 7.24 (1H, d, J=8.7 Hz); ¹⁹F NMR (DMSO-d₆): δ-21670,-21722, -4651 ; purity: 100% ; MS (m/e): 495 (MH+). 7.3.916N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R940353) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand methyl 5-aminobenzofuran-2-carboxylate were reacted to produceN4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940353. ¹H NMR (DMSO-d₆): δ12.05 (1H, s), 9.69 (1H, s), 9.43 (1H, s),8.28 (1H, s), 8.25 (1H, d, J=3.6 Hz), 7.40-7.64 (4H, m), 7.54 (1H, s),7.38 (1H, d, J=9 Hz), 3.97 (3H, s) ; ¹⁹F NMR (DMSO-d₆): δ-21707, -46489; purity: 97.77% ; MS (m/e): 486 (MH+). 7.3.917N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R940354) In like manner to the preparation of5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine,2-chloro-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-4-pyrimidineamineand methyl 5-aminobenzofuran-2-carboxylate were reacted to produceN4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamineR940354.¹H NMR (DMSO-d₆): δ10.75 (1H, s), 9.67 (1H, s), 9.53 (1H, s), 8.25 (1H,s), 8.21 (1H, d, J=4.2 Hz), 7.66 (2H, s), 7.59 (1H, s), 7.31 (1H, d,J=8.7 Hz), 7.26 (1H, s), 7.03 (1H, d, J=8.1 Hz), 3.97 (3H, s), 1.52 (6H,s) ; purity: 95.58% ; MS (m/e): 478 (MH+). 7.3.918N2,N4-Bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950244) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN2,N4-bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine.¹H NMR (MeOD, 300 MHz): δ8.65 (d, 1H, J =2.4 Hz), 7.15-7.58 (m, 8H),2.24 (s, 3H), 2.22 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H); LCMS: ret. time:17.03 min.; purity: 87.0%; MS (m/e): 478.89 (MH⁺). 7.3.919N4-(3-N,N-Diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950245) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-(3-N,N-diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.¹H NMR (MeOD, 300 MHz): δ8.65 (d, 1H, J =2.4 Hz), 7.03-7.66 (m, 8H),2.21 (s, 6H), 2.14 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H); LCMS: ret. time:19.27 min.; purity: 92.6%; MS (m/e): 521.01 (MH⁺). 7.3.920N4-(3-N-Acetylaminophenyl)-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950246) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-[3-N-acetylaminophenyl]-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.¹H NMR (MeOD, 300 MHz): δ8.66 (d, 1H, J =2.4 Hz), 6.88-7.57 (m, 8H),2.22 (s, 6H), 2.11 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H); LCMS: ret. time:18.89 min.; purity: 83.0%; MS (m/e): 520.97 (MH⁺). 7.3.921N2,N4-Bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950247) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN2,N4-bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine.¹H NMR (MeOD, 300 MHz): δ8.58 (d, 1H, J =2.4 Hz), 6.75-7.53 (m, 8H),2.04 (s, 3H), 2.03 (s, 3H), 2.01 (s, 6H), 1.99 (s, 6H); LCMS: ret. time:21.51 min.; purity: 91.8%; MS (m/e): 563.00 (MH⁺). 7.3.922N4-(3-Nitrophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950261) A mixture of equimolar amounts of2-chloro-N4-(3-nitrophenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(3-nitrophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 92.7%; MS (m/e): 412.94 (MH⁺). 7.3.923N4-(3-Aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineHCl salt (R950262)N4-(3-Nitrophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine and Pd/C 10% (50% water content) weresuspended in EtOH-10% aqueous HCl (1 : 1) and hydrogenated in a Parrapparatus for 2 hours (22° C., 50 psi). The suspension was filtered overcelite and carefully washed with MeOH. The combined filtrates wereconcentrated under reduced pressure to give the HCl salt ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 92.7%; MS (m/e): 383.07 (M-Cl⁺, 100).7.3.924N4-(3-Aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950263) The HCl salt ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewas neutralized with aqueous sodium carbonate solution and extractedwith EtOAc. The organic phase was dried and concentrated to giveN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a pale yellow solid. ¹H NMR (DMSO): δ10.00 (s, 1H), 9.92 (s, 1H),8.07 (d, 1H, J=2.4 Hz), 8.15 (bs, 2H), 7.91-8.07 (m, 3H), 7.08-7.21 (m,5H), 6.56 (d, 1H, J =7.2 Hz), 4.32 (s, 2H), 2.72 (d, 3H, J =4.8 Hz);LCMS: purity: 92.7%; MS (m/e): 383.17 (MH⁺, 100). 7.3.925N4-(3-Bis-N-methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950264) A solution ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DME-DMF (1 : 1) was treated with 10 equivalents of MeI and sodiumbicarbonate. The mixture was stirred for 1.5 hours at 70° C. andpurified by flash chromatography on silica gel to giveN4-(3-bis-N-methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 90.2%; MS (m/e): 411.04 (MH⁺, 100).7.3.926N4-(3-N-Hydroxyethylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950265) A solution ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DME-DMF (1 : 1) was treated with 10 equivalents of 2-bromoethanol andsodium bicarbonate. The mixture was stirred for 16 hours at 70° C. andpurified by flash chromatography on silica gel to giveN4-(3-N-hydroxyethylaminophenyl)-5-fluoro. LCMS: purity: 90.2%; MS(m/e): 427.33 (MH⁺, 100). 7.3.927N4-(3-Bis(N-hydroxyethyl)aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950266) A solution ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DME-DMF (1 : 1) was treated with 10 equivalents of 2-bromoethanol andsodium bicarbonate. The mixture was stirred for 16 hours at 70° C. andpurified by flash chromatography on silica gel to giveN4-(3-bis(N-hydroxyethyl)aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 94.2%; MS (m/e): 471.46 (MH⁺, 100).7.3.928N4-(3-N-Methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950267) A solution ofN4-(3-aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DME-DMF (1 : 1) was treated with 10 equivalents of MeI and sodiumbicarbonate. The mixture was stirred for 1.5 hours at 70° C. andpurified by flash chromatography on silica gel to giveN4-(3-N-methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 92.3%; MS (m/e): 397.02 (MH⁺, 100).7.3.929N4-(3-Carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950290) A mixture of equimolar amounts of2-chloro-N4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-4-aminopyridine and3-ethoxycarbonylmethyleneoxyaniline in MeOH in a pressure tube at 110°C. for 24 h or in EtOH using microwave at 175° C. for 10-20 min followedby aqueous work up gaveN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 97.8%; MS (m/e): 443.20 (MH⁺). 7.3.930N4-(3-Carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine(R950291) The reaction ofN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(0.1 g) and LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h atroom temperature followed by treatment with aqueous HCl gave the solid.The resulting solid was filtered, washed with water and dried to giveN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 91.5%; MS (m/e): 415.16 (MH⁺). 7.3.931N4-(3-Methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950293) A solution ofN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a 4 M solution of HCl in dioxane. Themixture was stirred for 1 hour at 22° C., concentrated to dryness andpurified by flash chromatography on silica gel to giveN4-(3-methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 96.8%; MS (m/e): 457.25 (MH⁺). 7.3.932N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950294) A mixture of equimolar amounts of2-chloro-N4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-4-aminopyridineand 3-ethoxycarbonylmethyleneoxyaniline in EtOH using microwave at 175°C. for 10-20 min followed by aqueous work up gaveN4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 92.1%; MS (m/e): 469.26 (MH⁺). 7.3.933N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950295) A mixture of equimolar amounts of2-chloro-N4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-4-aminopyridineand 3-ethoxycarbonylmethyleneoxyaniline in MeOH in a pressure tube at110° C. for 24 h followed by aqueous work up gaveN4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 87.6%; MS (m/e): 455.26 (MH⁺). 7.3.934N4-(4-Ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950296) A solution ofN4-(4-ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein EtOH was treated with the HCl salt of methylamine. The mixture wasstirred for 4 hours at 100° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 87.4%; MS (m/e): 468.29 (MH⁺). 7.3.935N4-(4-Carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950344) A mixture of equimolar amounts of2-chloro-N4-(4-carboxyethyleneoxyphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(4-carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 97.8%; MS (m/e): 456.32 (MH⁺). 7.3.936N4-(2,3-Dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950345) A solution ofN4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein TfOH was heated for 2 hours at 100° C. Aqueous work up followed byflash chromatography on silica gel gaveN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 92.2%; MS (m/e): 435.95 (MH⁺). 7.3.937N4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950346) A solution ofN4-(4-carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a 4 M solution of HCl in dioxane. Themixture was stirred for 1 hour at 22° C., concentrated to dryness andpurified by flash chromatography on silica gel to giveN4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 85.2%; MS (m/e): 468.01 (MH⁺). 7.3.938N4-(4-Hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950347) The reaction ofN4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h at roomtemperature followed by treatment with aqueous HCl gave a pale yellowsolid. The resulting solid was filtered, washed with water and dried togiveN4-(4-hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 94.7%; MS (m/e): 382.03 (MH⁺). 7.3.939N4-(2,3-Dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950348) A mixtureN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.5%; MS (m/e): 451.00 (MH⁺). 7.3.940N4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950349) A solution ofN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a sodiumcyanoborohydride. The mixture wasstirred for 1 hour at 22° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.19 (s, 1H), 9.09 (s, 1H), 8.03 (d,1H, J=2.4 Hz), 7.28-7.93 (m, 5H), 7.07 (t, 1H, J =7.2 Hz), 6.71 (d, 1H,J =7.2 Hz), 6.44 (dd, 1H, J =2.6, 7.2 Hz), 5.31 (d, 1H, J =5.1 Hz),4.14-4.59 (m, 3H), 4.30 (s, 2H), 2.63 (d, 3H, J =4.8 Hz), 1.82-2.03 (m,2H); LCMS: purity: 93.3%; MS (m/e): 440.15 (MH⁺). 7.3.941N4-(2,3-Dihydro-4-O-methyloxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950356) A mixtureN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand methoxyamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine as a white solid. LCMS: purity: 85.5%;MS (m/e): 465.10 (MH⁺). 7.3.942N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950368) A mixtureN4-(4-azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand Pd/C (10%) in MeOH was hydrogenated at 22° C. for 6 hours (40 psi).The mixture was filtered and concentrated to dryness to giveN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.60 (s, 1H), 9.46 (s, 1H), 8.73 (bs,3H), 8.00-8.10 (m, 3H), 7.47 (s, 1H), 7.42 (m, 1H), 7.29 (d, 1H, J =7.2Hz), 7.11 (t, 1H, J =7.2 Hz), 6.82 (d, 1H, J 7.0 Hz), 6.46 (m, 1H),4.23-4.46 (m, 3H), 4.31 (s, 3H), 2.63 (d, 3H, J =4.8 Hz), 2.09-2.29 (m,2H); LCMS: purity: 97.6%; MS (m/e): 438.98 (MH⁺). 7.3.943N4-(3-Methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950371) A mixture of equimolar amounts of2-chloro-N4-(3-methylcarbonylphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(3-methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ10.16 (s, 1H), 9.82 (s, 1H), 8.24 (d,1H, J=2.4 Hz), 8.15 (s, 1H), 7.91-8.07 (m, 2H), 7.70 (d, 1H, J=7.0 Hz),7.49 (t, 1H, J =7.2 Hz), 7.08-7.21 (m, 3H), 6.56 (d, 1H, J =7.2 Hz),4.30 (s, 3H), 2.62 (d, 3H, J =4.8 Hz), 2.48 (s, 3H); LCMS: purity:93.8%; MS (m/e): 410.50 (MH⁺). 7.3.944N4-(3-Phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950372) A mixture of equimolar amounts of2-chloro-N4-(3-phenylcarbonylphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(3-phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 86.0%; MS (m/e): 472.50 (MH⁺). 7.3.945N4-(3-Methylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950373) A mixtureN4-(3-methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(3-methylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ11.21 (s, 1H), 10.11 (s, 1H), 9.85 (s,1H), 6.54-8.23 (m, 9H), 4.32 (s, 2H), 2.63 (d, J =7.0 Hz, 3H), 2.47 (s,3H); LCMS: purity: 92.4%; MS (m/e): 425.28 (MH⁺). 7.3.946N4-(3-Phenylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950374) A mixtureN4-(3-phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(3-phenylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ11.63 (s, 1H), 10.30 (s, 1H), 9.85 (s,1H), 6.44-8.43 (m, 14H), 4.42 (s, 2H), 2.63 (d, J =7.0 Hz, 3H); LCMS:purity: 92.4%; MS (m/e): 487.31 (MH⁺). 7.3.947N2,N4-Bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950376) A mixture of 2,4-dichloro-5-fluoropyridine and threeequivalents of 3-acetophenone in MeOH in a pressure tube at 110° C. for24 h or in EtOH using microwave at 175° C. for 10-20 min followed byaqueous work up gaveN2,N4-bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine as awhite solid. LCMS: purity: 93.1%; MS (m/e): 365.19 (MH⁺). 7.3.948N2,N4-Bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950377) A mixture of 2,4-dichloro-5-fluoropyridine and threeequivalents of 3-benzophenone in MeOH in a pressure tube at 110° C. for24 h or in EtOH using microwave at 175° C. for 10-20 min followed byaqueous work up gaveN2,N4-bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine as awhite solid. LCMS: purity: 95.7%; MS (m/e): 489.29 (MH⁺). 7.3.949N2,N4-Bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950378) A solution ofN2,N4-bis(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminein TfOH was heated for 2 hours at 100° C. Aqueous work up followed byflash chromatography on silica gel gaveN2,N4-bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.36 (s, 1H), 9.14 (s, 1H), 8.06 (d,1H, J=2.4 Hz), 7.72-7.99 (m, 3H), 6.97 (d, J =7.2 Hz, 1H), 6.87 (d, J=7.2 Hz, 1H), 4.42-4.52 (m, 4H), 2.70-2.78 (m, 4H); LCMS: purity: 94.3%;MS (m/e): 484.50 (MH⁺). 7.3.950N2,N4-Bis(3-methylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine(R950379) A mixture ofN2,N4-bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine andhydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(3-methylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. ¹H NMR (DMSO): δ11.21 (s, 1H), 10.11 (s, 1H), 9.85 (s,1H), 6.54-8.23 (m, 9H), 4.32 (s, 2H), 2.63 (d, J =7.0 Hz, 3H), 2.47 (s,3H); LCMS: purity: 92.1%; MS (m/e): 393.06 (M-H⁻). 7.3.951N2,N4-Bis(3-phenylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine(R950380) A mixture ofN2,N4-bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine andhydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(3-phenylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. LCMS: purity: 93.3%; MS (m/e): 486.05 (M-H⁻). 7.3.952N2,N4-Bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950381) A mixture ofN2,N4-bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamineas a white solid. LCMS: purity: 98.1%; MS (m/e): 449.03 (M-H⁻). 7.3.953N4-(4-Acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950382) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein pyridine was treated with acetic anhydride at 22° C. for 16 hours.Aqueous work up gaveN4-(4-acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine as a white solid. ¹H NMR (DMSO): δ10.43(bs, 1H), 9.62 (bs, 1H), 8.03 (d, 1H, J =2.4 Hz), 7.10-7.83 (m, 7H),6.83 (d, 1H, J =7.4 Hz), 6.52 (d, 1H, J =7.2 Hz), 5.01 (m, 1H), 4.75 (s,2H), 4.03-4.32 (m, 2H), 2.62 (s, 3H), 2.23 (s, 3H), 1.93-2.13 (m, 2H);LCMS: purity: 92.1%; MS (m/e): 393.06 (M-H⁻). 7.3.954N4-(4-Azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950383) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry THF was treated with 2 equivalents of DPPA and DBU. The mixturewas stirred for 3 hours at 22° C., concentrated to dryness and purifiedby flash chromatography on silica gel to giveN4-(4-azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ10.09 (bs, 1H), 9.83 (bs, 1H), 8.18(d, 1H, J =2.4 Hz), 7.97 (m, 1H), 7.11-7.61 (m, 6H), 6.82 (d, 1H, J =7.8Hz), 6.62 (d, 1H, J =7.2 Hz), 4.78 (s, 2H), 4.03-4.33 (m, 3H), 2.62 (s,3H), 1.93-2.13 (m, 2H); LCMS: purity: 97.9%; MS (m/e): 463.07 (MH⁺).7.3.955N4-(4-Benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950385) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein THF was treated with bortrifluoride etherate at 80° C. for 8 hours.Aqueous work up gaveN4-(4-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.18 (s, 1H), 9.14 (s, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.93 (bs, 1H), 5.86-7.48 (m, 9H) 4.73-4.74 (m, 2H), 4.33(s, 2H), 2.62 (s, 3H); LCMS: purity: 96.5%; MS (m/e): 420.07 (M-H⁻).7.3.956N4-(3-Hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950386) A mixture of equimolar amounts of2-chloro-N4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethylene oxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.2%; MS (m/e): 410.5 (MH⁺). 7.3.957N4-(3-Amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950388) A mixture of2-chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-aminopyridine and 3equivalents of 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in apressure tube at 110° C. for 24 h or in EtOH using microwave at 175° C.for 10-20 min followed by aqueous work up gaveN4-(3-amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 95.1%; MS (m/e): 427.18 (MH⁺). 7.3.958N4-(4-Ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950389) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein HOAc was treated with sodium nitrate followed by addition ofconcentrated aqueous HCl and copper dichloride. The mixture was stirredfor 2 hours at 22° C. for 8 hours and purified by aqueous work upfollowed by column chromatography on silica gel to giveN4-(4-ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 82.3%; MS (m/e): 474.09 (M-H⁻). 7.3.959N2,N4-Bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950391) A mixture of 2,4-dichloro-5-fluoropyridine and threeequivalents of 3-methoxycarbonyl-4-trifluoromethoxyaniline in MeOH in apressure tube at 110° C. for 24 h or in EtOH using microwave at 175° C.for 10-20 min followed by aqueous work upN2,N4-bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.96 (s, 1H), 9.82 (s, 1H), 8.16-8.26(m, 4H), 7.91 (dd, 1H, J =3.0, 7.2 Hz), 7.42 (d, 1H, J=7.2 Hz), 7.31 (d,1H, J=7.2 Hz), 3.77 (s, 3H), 3.75 (s, 3H); LCMS: purity: 93.0%; MS(m/e): 565.37 (MH⁺). 7.3.960N4-(3-Methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950392) A mixture of equimolar amounts of2-chloro-N4-(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 95.8%; MS (m/e): 510.41 (MH⁺). 7.3.961N4-(4-Acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950393) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeCN was treated with concentrated sulfuric acid. The mixture wasstirred for 3 hours at 22° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ10.46 (bs, 1H), 9.52 (bs, 1H), 7.98(d, 1H, J =2.4 Hz), 7.12-7.73 (m, 7H), 6.66 (d, 1H, J =7.2 Hz), 6.49 (d,1H, J =7.2 Hz), 4.75 (s, 2H), 4.03-4.32 (m, 2H), 3.80 (m, 1H), 2.64 (s,3H), 2.143 (s, 3H), 1.90-2.11 (m, 2H); LCMS: purity: 92.1%; MS (m/e):393.06 (M-H⁻). LCMS: purity: 96.2%; MS (m/e): 479.13 (M-H⁻). 7.3.962N4-[2,4-Dihydro-1-oxo-4H-imidazo[2,1-c][1,4]benzoxazin-8-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R945236)N4-[2H-1,4-Benzoxazin-3(4H)-one-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(800 mg, 2.18 mmol) and phosphorus pentasulfide (800 mg, 1.80 mmol) werestirred in pyridine (5 mL) at 70° C. for 2 h. The reaction solution wastreated with 1N HCl solution to pH 5. The precipitation was collectedwith filtration, washed with water, dried to giveN4-[2H-1,4-benzoxazin-3(4H)-thione-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.7.3.9635-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-oxo-1,2,3,6-tetrahydropyrimido[2,1-c][1,4]benzoxazin-9-yl]-2,4-pyrimidinediamine(R945237) In a manner analogous to the preparation ofN4-[2,4-dihydro-1-oxo-4H-imidazo[2,1-c][1,4]benzoxazin-8-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-[2H-1,4-benzoxazin-3(4H)-thione-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(400 mg, 1.04 mmol) and β-alanine (500 mg) gave5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-oxo-1,2,3,6-tetrahydropyrimido[2,1-c][1,4]benzoxazin-9-yl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (acetone-d₆): δ2.68 (t, J=7.2 Hz, 2H), 3.71 (t,J=7.2 Hz, 2H), 4.62 (t, J=1.2 Hz, 2H), 6.42 (ddd, J=1.2 and 2.4 and 7.5Hz, 1H), 6.98-7.08 (m, 3H), 7.38 (t, J=2.4 Hz, 1H), 7.62 (dd, J=2.4 and8.7 Hz, 1H), 7.96 (d, J=3.3 Hz, 1H), 8.12 (s, 1H), 8.16 (s, 1H), 8.52(d, J=2.7 Hz, 1H), 8.65 (s, 1H); ¹⁹F NMR (282 MHz, acetone-d₆): δ-168.04. 7.3.9645-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine(R945242) 2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (500 mg) was treatedwith nitric acid (5 mL) and sulfuric acid (5 mL). The reaction mixturewas heated to 70° C. for 30 min and then poured into ice-water. Thesolution was neutralized with sodium bicarbonate to pH 6. The yellowprecipitation was collected by filtration, washed with water and driedto give a mixture of nitrated products (regio-isomers). The mixture ofnitrated compounds was reduced under hydrogenolysis conditions using 10%Pd-C in methanol at 40 psi for 30 min. The catalyst was filtered off.The filtrate was evaporated and treated with2,4-dichloro-5-fluoropyrimidine (200 mg) in methanol (5 mL), water (5mL). The reaction mixture was heated at 70° C. overnight, thenevaporated. The residue was reacted with3-methylaminocarbonylmethyleneoxyaniline (300 mg) in methanol (5 mL) andwater (1 mL) at 100° C. overnight. The reaction mixture was diluted with1N HCl solution (60 mL). The brown precipitation was collected byfiltration, washed with water and dried to give5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ2.62 (d, J=4.8 Hz, 3H), 4.33 (s, 2H), 4.63 (s, 2H),6.48 (dd, J=2.4 and 7.5 Hz, 1H), 7.11 (t, J=8.1 Hz,1H), 7.27 (d, J=7.8Hz, 1H), 7.36 (s, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.97 (m, 1H), 8.12 (d,J=3.6 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 9.33 (s, 1H), 9.46 (s, 1H), 11.18(s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 164.49; LCMS: ret. time: 13.16min.; purity: 79.30%; MS (m/e): 440.16 (MH⁺). 7.3.9655-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-7-yl]-2,4-pyrimidinediamine(R945263) 2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g, 6.66 mmol) wasrefluxed with boron hydride methyl sulfide complex (2 mL) in THF (10 mL)for 30 min to give 2H-pyrido[3,2-b]-1,4-oxazine. In a manner analogousto the preparation of5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine,2H-pyrido[3,2-b]-1,4-oxazine was nitrated, reduced and reacted with2,4-dichloro-5-fluoropyrimidine (400 mg) and3-methylaminocarbonylmethyleneoxyaniline (500 mg) to give5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-7-yl]-2,4-pyrimidinediamineas a gray solid. ¹H NMR (CDCl₃): δ2.91 (d, J=4.8 Hz, 3H), 3.55 (t, J=4.2Hz, 2H), 4.24 (t, J=4.5 Hz, 2H), 4.49 (s, 2H), 4.90 (br, 1H), 6.51 (dd,J=2.7 and 8.1 Hz, 1H), 6.64 (s,1H), 6.90 (dd, J=2.1 and 8.1 Hz, 1H),7.08 (s, 1H), 7.14 (br, 1H), 7.18 (t, J=8.1 Hz, 1H), 7.28 (d, J=2.1 Hz,1H), 7.51 (t, J=2.1 Hz, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.95 (d, J=2.4 Hz,1H); LCMS: ret. time: 11.91 min.; purity: 100%; MS (m/e): 426.12 (MH⁺).7.3.9665-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-2,4-pyrimidinediamine(R921304) 2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.5 g) was dissolved inacetic acid (6 mL) and acetic anhydride (30 mL). Fuming nitric acid (3mL) was added dropwise to the reaction solution in ice-bath. Thereaction solution was stirred in ice-bath overnight. Solution was pouredinto crashed ice. The light yellow precipitation was collected byfiltration, washed with water and dried to give a mixture of nitratedproducts (regio-isomers). The mixture was crystallized fromdichloromethane to give 6-nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1g) as a light yellow solid.6-Nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g) was reduced underhydrogenolysis conditions using 10% Pd-C in methanol (50 mL) and 1N HClsolution (10 mL) at 50 psi for 2 h. The catalyst was filtered off andwashed with methanol and 1N HCl solution. The filtrate was evaporated togive 6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one. In a manneranalogous to the preparation of5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine,6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one was reacted with2,4-dichloro-5-fluoropyrimidine (500 mg) and3-methylaminocarbonylmethyleneoxyaniline (500 mg) to give5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-2,4-pyrimidinediamineas a beige solid. ¹H NMR (DMSO-d₆): δ2.63 (d, J=4.5 Hz, 3H), 4.35 (s,2H), 4.62 (s, 2H), 6.47 (dd, J=1.8 and 8.1 Hz, 1H), 7.10 (t, J=8.1Hz,1H), 7.25 (d, J=8.1 Hz, 1H), 7.37 (m, 2H), 7.59 (d, J=8.4 Hz, 1H),7.96 (d, J=5.1 Hz, 1H), 8.13 (d, J=3.6 Hz, 1H), 9.26 (s, 1H), 9.29 (s,1H), 11.13 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 163.20; LCMS: ret.time: 25.22 min.; purity: 97.55%; MS (m/e): 440.25 (MH⁺). 7.3.9675-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-6-yl]-2,4-pyrimidinediamine(R945299) 6-Nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (500 mg) wasrefluxed with boron hydride methyl sulfide complex (1 mL) in THF (10 mL)for 30 min to give 6-nitro-2H-pyrido[3,2-b]-1,4-oxazine. In a manneranalogous to the preparation of5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine,6-nitro-2H-pyrido[3,2-b]-1,4-oxazine was reduced and reacted with2,4-dichloro-5-fluoropyrimidine (500 mg) and3-methylaminocarbonylmethyleneoxyaniline (500 mg) to give5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-6-yl]-2,4-pyrimidinediamineas a gray solid. ¹H NMR (CD₃OD): δ2.81 (s, 3H), 3.48 (t, J=4.5 Hz, 2H),4.14 (t, J=4.5 Hz, 2H), 4.44 (s, 2H), 6.60 (ddd, J=1.5 and 2.7 and 7.5Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.17 (t, J=7.8Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.42 (t, J=2.1 Hz, 1H), 7.92 (d, J=3.3Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ- 168.20; LCMS: ret. time: 25.49min.; purity: 97.56%; MS (m/e): 426.23 (MH⁺). 7.3.968 N4-(1,4-Benzoxazin-3-on-7-yl))-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R908698): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,4-benzoxazin-3-on-7-yl)pyrimidineamine and3-aminophenol were reacted to yieldN4-(1,4-Benzoxazin-3-on-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.1H (DMSO-d₆) 8.2 (d, 1H, J=4 Hz), 7.30 (m, 2H), 7.09 (m, 4H), 6.5 (m,1H), 4.6 (s, 2H) purity 95 %; MS (m/e): 368 (MH+) 7.3.969N2-(1,4-Benzoxazin-3-on-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R908699): In likemanner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)]pyrimidineamine and7-amino-1,4-benzoxazine-3-one were reacted to yieldN2-(1,4-Benzoxazin-3-on-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H (DMSO-d₆) 8.20(d, 1H, J=4 Hz), 7.10 (m, 5H), 6.65 (m, 1H), 4.54 (s, 2H) purity 95 % MS(m/e): 368 (MH+) 7.3.970 N4-(1,4-Benzoxazine-3-on-7-yl)-5-fluoro-N2-((N-methyl acetamido-2)-3-phenoxy)-2,4-pyrimidinediamine (R908700): Inlike manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-1,4-benzoxazin-3-on-7-yl)phenylpyrimidineamine and3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yieldN4-(1,4-Benzoxazine-3-on-7-yl)-5-fluoro-N2-( (N-methylacetamido-2)-3-phenoxy)-2,4-pyrimidinediamine 1H (DMSO-d₆) 8.2 (d, 1H,J=4 Hz), 8.00 (m, 1H), 7.19 (m, 1H), 7.09 (m, 3H), 6.55 (m, 1H), 4.64(s, 2H), 4.27 (s, 2H), 3.18 (s, 3H), 2.63 (m, 3H) purity 95 % MS(m/e):439 (MH+) 7.3.971N4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-[(N-methylacetamido-2)-3-phenoxy)]-2,4-pyrimidinediamine (R908701): In like mannertoN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[6-(1,4-benzoxazin-3-onyl)]phenylpyrimidineamineand 3-(N- methylaminocarbonylmethyleneoxy)aniline were reacted to yieldN4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-[(N-methylacetamido-2)-3-phenoxy]-2,4-pyrimidinediamine 1H (DMSO-d₆) 8.2 (d, 1H,J=4 Hz), 8.00 (m, 1H), 7.13 (m, 3H), 6.95 (m, 1H), 6.55 (m, 1H), 4.64(s, 2H), 4.27 (s, 2H), 3.18 (s, 3H), 2.63 (m, 3H) purity 96 % MS (m/e):439 (MH+) 7.3.972 N4-(1,4-Benzoxazine-3-on-6-yl)- 5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R908702): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(1,4-benzoxazin-3-on-6-yl)phenylpyrimidineamine and3-aminophenol were reacted to yield N4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-( 3-hydroxyphenyl)-2,4-pyrimidinediamine 1H (DMSO-d₆) 8.20(d, 1H, J=4 Hz), 7.22 (m, 2H), 7.03 (m, 4H), 6.55 (m, 1H), 4.64 (s, 2H)purity 98 %MS (m/e): 368 (MH+) 7.3.973 5-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazine-3-on-6-yl)-2,4-pyrimidinediamine (R908703):In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)]phenylpyrimidineamineand 3-(N- methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)]pyrimidinediamine1H (DMSO-d₆) 8.20 (d, 1H, J=4 Hz), 7.23 (m, 6H), 6.55 (m, 1H), 4.64 (s,2H), 3.18 (s, 3H) purity 96 %; MS (m/e): 382(MH+) 7.3.9745-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine (R908704): In likemanner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]phenylpyrimidineamineand 3-(N- methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine 1H (DMSO-d₆) 8.8.13(d, 1H, J=4 Hz), 7.13 (m, 3H), 6.72 (m, 3H), 6.59 (m, 1H), 4.24 (m, 2H),4.27 (s, 2H), 3.28 (m, 2H), 2.83 (m, 3H) purity 93 %; MS (m/e): 367(MH+) 7.3.975 5-Fluoro-N2-[(N-methyl acetamido-2)-3-phenoxy]-N4-(N-methyl-1,4-benzoxazin-7-yl)- 2,4-pyrimidinediamine (R908705): Inlike manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N2-[(N-methyl acetamido-2)-3-phenoxy]-N4-(N-methyl-1,4-benzoxazin-7-yl)- 2,4-pyrimidinediamine 1H (DMSO-d₆)8.20 (d, 1H, J=4 Hz), 7.13 (m, 5H), 6.75 (m, 2H), 4.44 (s, 2H), 4.27 (m,2H), 3.22 (m, 2H), 2.83 (s, 3H), 2.63 (m, 3H) purity 96 %; MS (m/e): 439(MH+) 7.3.976 N2-( 1,4-Benzoxazin-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R908706): In likemanner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)]pyrimidineamine and7-amino-1,4-benzoxazine were reacted to yield N2-( 1,4-Benzoxazin-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H (DMSO-d₆) 7.95(d, 1H, J=4 Hz), 7.43 (m, 1H), 7.02 (m, 4H), 6.42 (m, 2H), 4.17 (m, 2H),3.33 (m, 2H) purity 96 %; MS (m/e): 353 (MH+)] 7.3.977 5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine (R908707): In likemanner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( N-methyl-1,4-benzoxazin-7-yl)pyrimidineamine and3-aminophenol were reacted to yield 5-Fluoro-N2-( 3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine. 1H (DMSO-d₆) 8.20(d, 1H, J=4 Hz), 7.10 (m, 5H), 6.65 (m, 1H), 4.54 (s, 2H) purity 95 % MS(m/e): 368 (MH+) 7.3.978 5-Fluoro-N4-(3-hydroxyphenyl)N2-(N-Methyl-1,4-benzoxazine-3-on-7-yl)-2,4-pyrimidinediamine (R908708):In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)pyrimidineamine and7-amino-4-N-methyl-1,4-benzoxazine-3-one were reacted to yield5-Fluoro-N4-(3-hydroxyphenyl)N2-(N-Methyl-1,4-benzoxazine-3-on-7-yl)-2,4-pyrimidinediamine. 1H(DMSO-d₆) 8.20 (d, 1H, J=4 Hz), 7.23 (m, 1H), 7.15 (m, 5H), 6.62 (m,1H), 4.64 (s, 2H), 4.27 (s, 2H), 3.18 (s, 3H) purity 95 %; MS (m/e): 380(MH+)] 7.3.979 5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-2,4-pyrimidinediamine(R908709): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)]pyrimidineamine and6-amino-1,4-benzoxazine were reacted to yield 5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-2,4-pyrimidinediamine.1H (DMSO-d₆) 8.20 (d, 1H, J=4 Hz), 7.43 (m, 2H), 7.19 (m, 4H), 6.55 (m,1H), 4.64 (s, 2H), 3.25 (s, 3H) purity 95 %; MS (m/e): 382 (MH+) 7.3.9805-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamine(R908710): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)pyrimidineamine and6-amino-1,4-benzoxazine were reacted to yield 5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamine.1H (MeOD-d4) 8.20 (d, 1H, J=4 Hz), 7.43 (m, 3H), 6.90 (m, 2H), 6.75 (m,1H), 4.25 (m, 2H), 3.25 (m, 2H), 2.85 (bs, 1 H) purity 96 %; MS (m/e):382 (MH+) 7.3.981 N4-(1,4-Benzoxazin-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-pyrimidinediamine (R908711): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-[6-(1,4-benzoxazinyl)]-N2-chloro-5-fluoropyrimidineamine and3-ethoxyocarbonylmethyleneoxyaniline were reacted to yieldN4-(1,4-Benzoxazin-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-pyrimidinediamine ¹H NMR (MeOD-d4): δ8.2 (d, 1H, J=4 Hz), 7.15 (m, 4H),6.84 (m, 2H), 6.62 (m, 1H), 4.65 (s, 2H), 4.15 (m, 4H), 3.28 (m, 2H),1.19 (t, 3H. J=7 Hz) purity 94 %; MS (m/e): 439 (MH⁺). 7.3.982(+/-)-5-Fluoro-N2-[(N-methyl acetamido-2)-3-phenoxy]-N4-(2-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamine (R908712): Inlike manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(+/-)-2-chloro-5-fluoro-N4-(2-methyl-1,4-benzoxazin-6-yl)]phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield(+/-)-5-Fluoro-N2-[(N-methyl acetamido-2)-3-phenoxy]-N4-(2-methyl-1,4-benzoxazin-6-yl)- 2,4-pyrimidinediamine 1H (DMSO-d₆)8.20 (d, 1H, J=4 Hz), 8.13 (m, 1H), 7.1 (m, 5H), 6.96 (m, 1H), 6.63 (m,1H), 4.62 (m, 1H), 4.40 (s, 3H), 2.63 (m, 3H), 1.25 (m, 3H) purity 93 %;MS (m/e): 453 (MH+) 7.3.983N2-(N-Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-hydroxyphenyl)phenyl]pyrimidinediamine(R908734): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-Chloro-5-fluoro-N4-(3-hydroxyphenyl)pyrimidineamine and6-Amino-N-carbomethoxy-1,4-benzoxazine were reacted to yieldN2-(N-Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-hydroxyphenyl)phenyl]pyrimidinediamine1H NMR (DMSO-d₆): δ8.23 (m, 1H), 7.20 (m, 1H), 7.14 (m, 4H), 6.95(m,1H), 6.76 (m, 1H), 4.66 (s, 1H), 4.48 (s, 1H), 4.25 (q, 2H J=6.5 Hz),1.28 (t, 2H, J=6.5 Hz), purity 95 % MS (m/e): 454(MH⁺). 7.3.984N4-(1,4-Benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoropyrimidinediamine(R909255): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-[6-(1,4-benzoxazinyl)]-N2-chloro-5-fluoropyrimidineamine and3-chloro-4-hydroxy-5-methylaniline were reacted to yieldN4-(1,4-benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoropyrimidinediamine¹H NMR (DMSO-d₆): δ7.89 (d, 1H, J=4 Hz), 7.25 (m, 1H), 7.14 (m, 1H),6.80 (m, 2H), 6.82 (m, 1H), 4.29 (s, 2H), 3.35 (m, 2H), 2.20 (s, 3H)purity 99 %; MS (m/e): 402 (MH⁺). 7.3.9855-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-6-yl)pyrimidinediamine(R909259): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[6-(N-methyl-1,4-benzoxazinyl)]phenylpyrimidineamine and 3-(N-methylaminocarbonylmethyleneoxy)aniline werereacted to yield5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-6-yl)pyrimidinediamine1H (DMSO-d₆) 8.01 (d, 1H, J=4 Hz), 7.33 (m, 2H), 7.22 (m, 1H), 7.02 (m,2H), 6.65 (m, 1H), 6.42 (m, 1H), 4.37 (s, 2H), 4.22 (m, 2H), 3.18 (m,2H), 2.78 (s, 3H) 2.63 (m, 3H) purity 98 %; MS (m/e): 439 (MH+) 7.3.9865-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-[6-(N-methyl-1,4-benzoxazin-3-onyl)]pyrimidinediamine(R909260): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[6-(N-methyl-1,4-benzoxazin-3-onyl)]phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-[6-(N-methyl-1,4-benzoxazin-3-onyl)]pyrimidinediamine1H (DMSO-d₆) 8.01 (d, 1H, J=4 Hz), 7.33 (m, 2H), 7.22 (m, 1H), 7.02 (m,2H), 6.65 (m, 1H), 6.42 (m, 1H), 4.37 (s, 2H), 4.22 (s, 2H), 3.18 (s,3H), 2.78 (s, 3H) 2.63 (m, 3H) purity 88%; MS (m/e): 453 (MH+) 7.3.9875-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]-2,4-pyrimidinediamine(R909261): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)phenylpyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)pyrimidinediamine1H (DMSO-d₆) 8.08 (d, 1H, J=4 Hz), 7.43 (m, 2H), 7.19 (m, 1H), 7.09 (m,3H), 6.55 (m, 1H), 4.64 (s, 2H), 4.27 (s, 2H), 3.18 (s, 3H), 2.63 (m,3H) MS (m/e): 453 (MH+) 7.3.988(+/-)-5-Fluoro-N4-(3-hydroxyphenyl]-N2-(2-methyl-1,4-benzothiazin-3-on-6-yl)pyrimidinediamine(R909263): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-( 3-hydroxyphenyl)pyrimidineamine and6-amino-2-methyl-1,4-benzothiazin-3-one were reacted to yield(+/-)-5-Fluoro-N4-(3-hydroxyphenyl]-N2-(2-methyl-1,4-benzothiazin-3-on-6-yl)pyrimidinediamine¹H NMR (MeOD-d4): δ8.02 (d, 1H, J=4 Hz), 7.30 (m, 3H), 7.08 (m, 3H),6.52 (m, 1H), 3.57 (m, 1H), 1.25 (m, 3H) purity 92 %; MS (m/e): 398(MH⁺). 7.3.9895-Fluoro-N2-[3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)-2,4-pyrimidinediamine(R909264): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]phenylpyrimidineamineand 3-aminophenol were reacted to yield5-Fluoro-N2-[3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]-2,4-pyrimidinediamine1H (DMSO-d₆) 8.08 (d, 1H, J=4 Hz), 7.53 (m, 2H), 7.09 (m, 4H), 6.42 (m,1H), 4.64 (s, 2H), 3.27 (s, 3H) purity 95 % MS (m/e): 382 (MH+) 7.3.990N4-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy) phenyl]pyrimidinediamine(R909265): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-Chloro-N4-(3-ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoropyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yieldN4-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]pyrimidinediamine ¹HNMR (DMSO-d₆): δ8.23 (m, 2H), 8.08 (d, J=4 Hz, 1H), 7.92 (m, 1H), 7.43(m, 1H), 7.38(m, 2H), 7.18 (m, 1H), 6.99 (t, 1H), 6.41 (m, 1H), 5.43 (s,2H) purity 92 %; MS (m/e): 534 (MH⁺). 7.3.991 N4-( 1,4-Benzoxazin-7-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R909266): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N4-(1,4-Benzoxazin-7-yl )-2-chloro-5-fluoro- pyrimidineamine and3-(ethoxycarbonylmethyleneoxy)aniline were reacted to yield N4-(1,4-Benzoxazin-7-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.1H (DMSO-d₆) 8.2 (d, 1H, J=4 Hz), 7.43 (m, 1H), 7.12 (m, 4H), 6.68 (m,2H), 4.7 (s, 2H) 4.17 (m, 2H), 3.33 (m, 2H), 3.13 (m, 2H) 1.87 (m, 3H)purity 89 %; MS (m/e): 439 (MH+) 7.3.992N2-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)pyrimidinediamine(R909267): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-Chloro-5-fluoro-N4-(3-hydroxyphenyl)pyrimidineamine and 3 Ethyl6-Amino-(3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine were reacted toyieldN2-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)pyrimidinediamine1H NMR (DMSO-d₆): δ8.18 (m, 1H), 8.04 (m, 1H), 7.38 (m, 1H), 7.22 (m,1H), 7.04 (m, 2H), 6.96 (m, 1H), 6.53 (m, 1H), 5.42 (s, 2H), 4.25 (q, 2HJ=6.5 Hz), 1.28 (t, 2H, J=6.5 Hz), purity 92 % MS (m/e): 409 (MH⁺).7.3.993 N2-(1,4-Benzoxazin-3-on-6-yl)- 5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R909268) In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineN4-[6-(1,4-benzoxazinyl)]-N2-chloro-5-fluoropyrimidineamine and6-amino-1,4-benzoxazin-3-one were reacted to yieldN2-(1,4-benzoxazin-3-on-6-yl)-5-fluoro-N4-(6-(1,4-benzoxazinyl)]-)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ8.18(d, 1H J=4 Hz), 7.17 (m, 2H), 6.88 (m, 2H ), 6.80 (m, 1H ), 6.58 (m, 1H)4.52 (s, 2H), 4.11 (m, 2H), 3.33 (m, 2H) purity: 97 %; MS (m/e): 409(MH⁺). 7.3.994 N2-[3-(N,N-Dimethylaminocarbonylmethyleneoxy)phenyl]-N4-(1,4-benzoxazin-6-yl)-5-fluoro--2,4-pyrimidinediamine(R909290) In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(1,4-benzoxazin-6-yl)-N2-(3-ethoxyocarbonylmethyleneoxyphenyl)-5-fluoro-pyrimidinediamineand dimethylamine hydrochloride were reacted to yieldN2-[3-(N,N-Dimethylaminocarbonylmethyleneoxy)phenyl]-N4-(1,4-benzoxazin-6-yl)-5-fluoro--2,4-pyrimidinediamine ¹H NMR (CD₃OD): δ7.8 (d, 1H), 7.4 (m,1H), 7.05 (m, 2H), 7.0 (s, 1H), 6.8 (dd, 1H), 6.66 (d, 1H), 6.56 (dd,1H), 4.35 (s, 2H), 4.18 (m, 2H), 3.25 (m, 2H), 2.8 (s, 6H); purity: 95%; MS (m/e): 439 (MH+) 7.3.995N4-(4N-Carboxamidino-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R909292) To a solution in 2 mL THF at 0°Celsius containing 250 mg (0.59mmol) ofN4-(1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,1.4 eq, 115 uL TEA, and catalytic DMAP was added 0.4 eq,70 mg oftriphosgene. After 30 min 15 mL of aqueous ammonia and stirred for 30min at RT. The THF was evaporated and the reaction was diluted withwater, and the resulting precipitate collection by suction filtration.The crude precipitate was purified by preparative TLC (5% MeOH/EtOAc) toyieldN4-(4N-Carboxamidino-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.83 (m, 1H), 7.42 (m, 1H), 7.12 (m, 2H), 7.08 (s, 1H),6.84 (m, 1H), 6.66 (m, 1H), 6.48 (m, 1H), 4.30 (s, 2H), 4.15 (m, 2H),3.22 (m, 2H), 2.82 (s, 3H); purity: 87 %; MS (m/e): 468 (MH⁺). 7.3.996N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine(R909308): In like manner toN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-Chloro-N4-(3,3-dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-pyrimidineamineand 3-(ethoxycarbonylmethyleneoxy)aniline were reacted to yieldN4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine.1H (DMSO-d₆) 8.00 (m, 1H), 7.43 (m, 2H), 7.05 (m, 1H), 6.82 (m, 2H),6.68 (m, 1H), 6.41 (m, 1H), 4.80 (s, 2H), 4.18 (q, 2H), 3.74 (s, 2 H),1.03 (t, 3H), 1.00 (s, 6H) purity 99 %; MS (m/e): 467 (MH+) 7.3.997N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R909309): In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine. 1H (DMSO-d₆) 8.04 (d, 1H),7.93 (m, 1H), 7.45 (m, 2H), 7.09 (m, 1H), 6.93 (m, 2H), 6.62 (m, 1H),6.43 (m, 1H), 4.37 (s, 2H), 3.74 (s, 2 H), 2.62 (d, 3H), 1.07 (s, 6H)purity 99 %; MS (m/e): 453 (MH+) 7.3.998N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R909309): In like manner toN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to yieldN4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine. 1H (DMSO-d₆) 8.04 (d, 1H),7.93 (m, 1H), 7.45 (m, 2H), 7.09 (m, 1H), 6.93 (m, 2H), 6.62 (m, 1H),6.43 (m, 1H), 4.37 (s, 2H), 3.74 (s, 2 H), 2.62 (d, 3H), 1.07 (s, 6H)purity 99 %; MS (m/e): 453 (MH+) 7.3.999N4-(2,4-Diiodo-3-hydroxypheny)-5-fluoro-N2-(3-iodo-1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine(R935221) To5-fluoro-N2-(3-hydroxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine(34.4 mg, 0.098 mmole) in ethanol (2.0 mL) and aq. NH₄OH (2.0 mL), I₂(0.126 g, 0.99 mmole atom) was added and stirred at room temperatureovernight. Reaction mixture was concentrated, dissolved in EtOAc andtreated with aq. hypo solution. Organic layer was separated, dried withanhydrous Na₂SO₄ and concentrated. The crude material was purified bysilica gel column chromatography to provideN4-(2,4-diiodo-3-hydroxypheny)-5-fluoro-N2-[3-iodo-1-methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.86 (s, 1H), 9.51 (s, 1H), 9.12(s, 1H), 8.28 (s,1H), 8.07 (d, 1H, J =3.5 Hz), 7.79 (s, 1H), 7.63 (s, 1H), 7.32 (d, 1H, J=8.8 Hz), 7.37 (d, 1H, J =8.8 Hz), 3.92 (s, 3H). LCMS: ret. time: 20.88min.; purity: 91%; MS (m/e): 729 (MH⁺). 7.3.10005-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935222) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 5-amino-1-(methoxycarbonyl)methylindazoline to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.17 (s, 1H), 9.13 (s, 1H), 8.10 (s, 1H), 8.03 (d,1H, J =4.1 Hz), 7.85 (s, 1H), 7.58 (d, 2H, J =8.8 Hz), 7.46 (s, 2H),6.87 (s, 2H, J =8.8 Hz), 5.31 (s, 2H), 4.57 (sep, 1H, J =5.8Hz), 3.65(s, 3H), 1.25 (d, 6H, J =5.8 Hz). LCMS: ret. time: 21.33 min.; purity:96%; MS (m/e): 451 (MH⁺). 7.3.1001 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935223) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro- 4-pyrimidineamine wasreacted with 5-amino-1-(methoxycarbonyl)methyl-indazoline to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.16 (s, 1H), 9.14 (s, 1H), 8.13 (s, 1H), 8.04 (d,1H, J =4.1 Hz), 7.89 (s, 1H), 7.48 (s, 2H), 7.30 (d, 1H, J =2.9 Hz),7.20 (dd, 1H, J =2.9 and 8.8 Hz), 6.79 (d, 1H, J =8.8 Hz), 5.32 (s, 2H),4.22 (s, 4H), 3.65 (s, 3H). LCMS: ret. time: 21.33 min.; purity: 96%; MS(m/e): 451 (MH⁺). 7.3.10025-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine(R935224) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.46 (s, 1H), 8.98 (s, 1H), 8.07 (d, 1H, J =4.1 Hz),8.02 (d, 1H, J =4.7 Hz), 7.98 (s, 2H), 7.66 (d, 1H, J =8.8 Hz), 7.50 (d,2H, J =8.8 Hz), 7.46 (app s, 1H), 6.74 (d, 2H, J =8.8 Hz), 4.96 (s, 2H),4.46 (sept, 1H, J =5.8 Hz), 2.58 (d, 3H, J =4.7 Hz), 1.21 (d, 6H, J =5.8Hz). LCMS: ret. time: 18.22 min.; purity: 93%; MS (m/e): 450 (MH⁺).7.3.1003 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine(R935225) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-(3,4-ethyelnedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.47 (s, 1H), 8.99 (s, 1H), 8.08 (d, 1H, J =3.5 Hz),8.06 (s, 1H), 8.01 (d, 1H, J =4.7 Hz), 7.98 (d, 1H, J =1.1 Hz), 7.66 (d,1H, J =8.8 Hz), 7.45 (dd, 1H, J =1.1 and 8.8 Hz), 7.31 (d, 1H, J =2.3Hz), 7.01 (dd, 1H, J =2.9 and 8.8 Hz), 6.66 (d, 1H, J =8.8 Hz), 4.95 (s,2H), 4.14 (s, 4H), 2.57 (d, 3H, J =4.1 Hz). LCMS: ret. time: 15.55 min.;purity: 94%; MS (m/e): 450 (MH⁺). 7.3.10045-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935237) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with5-amino-1-(methoxycarbonyl)methyl-indazoline to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.40 (s, 1H), 9.19 (s, 1H), 9.17 (s, 1H), 8.23 (s,1H), 8.07 (d, 1H, J =3.5 Hz), 7.90 (s, 1H), 7.47 (s, 2H), 7.25 (d, 1H, J=7.6 Hz), 7.11 (d, 1H, J =7.6 Hz), 7.08 (d, 1H, J =8.2 Hz), 6.53 (d, 1H,J =8.2 Hz), 5.31 (s, 2H), 3.64 (s, 3H). LCMS: ret. time: 15.82 min.;purity: 96%; MS (m/e): 409 (MH⁺). 7.3.1005 N2,N4-Bis[1-(2-hydroxyethyl)indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine(R935238) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2,N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce N2,N4-bis[1-(2-hydroxyethyl)indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.56 (s, 1H), 9.43 (s, 1H), 8.19 (d, 1H, J =3.5 Hz),8.06 (s, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.66 (d, 1H, J=8.8 Hz), 7.52 (d, 1H, J =8.8 Hz), 7.42 (dd, 1H, J =1.7 and 8.8 Hz),7.23 (dd, 1H, J =1.7 and 8.8 Hz), 4.75 (t, 1H, J =5.3 Hz), 4.68 (t, 1H,J =5.3 Hz), 4.09-4.02 (m, 2H), 3.81-3.74 (m, 2H), 3.63-3.60 (m, 2H),3.56-3.52 (m, 2H). LCMS: ret. time: 13.73 min.; purity: 90%; MS (m/e):449 (MH⁺). 7.3.10065-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935239) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.27 (s, 1H), 9.21 (s, 1H), 8.07 (s, 1H), 8.04 (d,1H, J =4.1 Hz), 7.90 (qt, 1H, J =4.7 Hz), 7.83 (s, 1H), 7.58 (d, 2H, J=8.8 Hz), 7.44 (s, 2H), 6.87 (d, 2H, J =8.8 Hz), 4.98 (s, 2H), 4.57 (q,1H, J =5.8 Hz), 2.59 (d, 3H, J =4.1 Hz), 1.21 (d, 6H, J =5.8 Hz). LCMS:ret. time: 17.74 min.; purity: 94%; MS (m/e): 450 (MH⁺). 7.3.1007 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935240) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.36 (br s, 2H), 8.06 (d, 1H, J =3.5 Hz), 8.05 (s,1H), 7.99 (qt, 1H, J =4.7Hz), 7.87 (s, 1H), 7.46 (s, 2H), 7.30-7.28 (m,1H), 7.20-7.17 (m, 1H), 6.79 (d, 1H, J =8.8 Hz), 4.99 (s, 2H), 4.22 (s,4H), 2.59 (d, 3H, J =4.7 Hz). LCMS: ret. time: 15.06 min.; purity: 91%;MS (m/e): 450 (MH⁺). 7.3.10085-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935242) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyrimidineaminewas reacted with 4-isopropoxyaniline to provide5-fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.58 (s, 1H), 10.09 (s, 1H), 8.23 (d, 1H, J =5.3Hz), 8.04 (s, 1H), 8.02 (s, 1H, J =5.8 Hz), 7.68 -7.63 (m 1H), 7.58-7.55(s, 1H), 7.30 (d, 2H, J =8.8 Hz), 6.82 (d, 2H, J =8.8 Hz), 5.41 (s, 2H),4.53 (sept, 1H, J =5.8 Hz), 3.66 (s, 3H), 1.21 (d, 6H, J =5.8 Hz). LCMS:ret. time: 19.30 min.; purity: 93%; MS (m/e): 451 (MH⁺). 7.3.1009 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935248) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 19.42 min.; purity: 94%; MS (m/e): 423 (MH⁺). 7.3.1010N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935249) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyridinaminewas reacted with 3, 4-ethylenedioxyaniline to provide N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.32 (s, 1H), 8.94 (s, 1H), 8.14 (d, 1H, J =4.7 Hz),8.03 (d, 1H, J =4.7 Hz), 8.01 (s, 1H), 7.65-7.57 (m, 2H), 7.23 (d, 1H, J=1.7 Hz), 7.02 (dd, 1H, J =1.9 and 8.8 Hz), 6.63 (d, 1H, J =8.8 Hz),5.38 (s, 2H), 4.14 (s, 4H), 3.66 (s, 3H). LCMS: ret. time: 18.94 min.;purity: 91%; MS (m/e): 451 (MH⁺). 7.3.10115-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine(R935250) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-4-pyrimidineaminewas reacted with 3-aminophenol to provide5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.34 (s, 1H), 9.16 (s, 1H), 8.25 (d, 1H, J =4.7 Hz),8.05 (d, 1H, J =4.7 Hz), 8.02 (s, 1H), 7.65-7.57 (m, 2H), 7.10 (d, 2H, J=5.8 Hz), 6.93 (d, 1H, J =8.8 Hz), 6.90 (d, 1H, J =8.8 Hz), 6.28 (app d,1H, J =8.8 Hz), 5.37 (s, 2H), 3.66 (s, 3H). LCMS: ret. time: 17.87 min.;purity: 97%; MS (m/e): 409 (MH⁺) 7.3.10125-Fluoro-N4-(4-isopropoxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935251) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 1-aminopyrrole to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.93 (s, 1H), 9.21 (s, 1H), 7.97 (d, 1H, J =4.1 Hz),7.47 (d, 2H, J =8.8 Hz), 6.70 (dd, 2H, J =2.3 and 4.7 Hz), 6.67 (d, 2H,J =8.8 Hz), 6.02 (dd, 2H, J =2.3 and 4.7 Hz), 4.48 (sept, 1H, J =5.8Hz), 1.21 (d, 6H, J =5.8 Hz). LCMS: ret. time: 23.44 min.; purity: 90%;MS (m/e): 328 (MH⁺). 7.3.1013 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935252) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 1-aminopyrrole to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.95 (s, 1H), 9.16 (s, 1H), 7.95 (d, 1H, J =3.5 Hz),7.16-7.12 (m, 2H), 6.69 (dd, 2H, J =2.3 and 4.7 Hz), 6.61 (d, 1H, J =8.8Hz), 5.99 (dd, 2H, J =2.3 and 4.7 Hz), 4.12-4.15 (m, 4H). LCMS: ret.time: 19.86 min.; purity: 92%; MS (m/e): 328 (MH⁺). 7.3.10145-Fluoro-N4-(3-hydroxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine(R935253) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with1-aminopyrrole to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.95 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), 7.99 (d,1H, J =3.5 Hz), 7.22 (d, 1H, J =8.2 Hz), 6.94 (br s, 1H), 6.89 (t, 1H, J=8.2 Hz), 6.70 (dd, 2H, J =2.3 and 4.7 Hz), 6.38 (d, 1H, J =8.2 Hz),5.99 (t, 2H, J =2.3 and 4.7 Hz). LCMS: ret. time: 18.23 min.; purity:94%; MS (m/e): 286 (MH⁺). 7.3.10155-Fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R935255) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.16 (s, 1H), 9.10 (s, 1H), 8.09 (s, 1H), 8.02 (s,1H, J =4.0 Hz), 7.79 (s, 1H), 7.59 (d, 2H, J =8.8 Hz), 7.48 (d, 1H, J=8.8 Hz), 7.42 (dd, 1H, J =1.7 and 8.8 Hz), 6.87 (d, 2H, J =8.8 Hz),4.83 (t, 1H, J =5.8 Hz), 4.57 (sept, 1H, J =5.8 Hz), 4.35 (t, 2H, J =5.8Hz), 3.75 (app qt, 2H, J =5.8 Hz), 1.26 (d, 6H, J =5.8 Hz). LCMS: ret.time: 20.90 min.; purity: 94%; MS (m/e): 423 (MH⁺). 7.3.10165-Fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R935256) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.39 (s, 1H), 9.18 (s, 1H), 9.14 (s, 1H), 8.19 (s,1H), 8.07 (d, 1H, J =4.1 Hz), 7.84 (s, 1H), 7.50-7.42 (m, 2H), 7.26 (d,1H, J =8.2 Hz), 7.12-7.06 (m, 2H), 6.52 (d, 1H, J =8.2 Hz), 4.83 (t, 1H,J =5.8 Hz), 4.35 (t, 2H, J =5.8 Hz), 3.75 (app qt, 2H, J =5.8 Hz). LCMS:ret. time: 15.97 min.; purity: 95%; MS (m/e): 381 (MH⁺). 7.3.1017 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935258) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.20 (s, 1H), 8.93 (s, 1H), 8.12 (s, 1H), 8.02 (d,1H, J =3.5 Hz), 7.94 (s, 1H), 7.59 (s, 2H), 7.23 (d, 1H, J =0.9 Hz),7.02 (dd, 1H, J =1.0 and 8.8 Hz), 6.64 (d, 1H, J =8.8 Hz), 4.86 (t, 1H,J =5.3 Hz), 4.40 (t, 2H, J =5.8 Hz), 4.15 (s, 4H), 3.78 (app qt, 2H, J=5.3 and 5.8 Hz). LCMS: ret. time: 18.07 min.; purity: 93%; MS (m/e):423 (MH⁺). 7.3.10185-Fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R935259) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediaminewas reacted with DIBAL-H to produce5-fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 9.16 (s, 1H), 9.01 (s, 1H), 8.23 (s,1H), 8.05 (d, 1H, J =3.5 Hz), 7.96 (s, 1H), 7.60 (s, 2H), 7.10 (app s,2H), 6.92 (t, 1H, J =8.8 Hz), 6.31 (d, 1H, J =8.8 Hz), 4.86 (t, 1H, J=5.3 Hz), 4.40 (t, 2H, J =5.8 Hz), 3.79 (app qt, 2H, J =5.3 and 5.8 Hz).LCMS: ret. time: 16.09 min.; purity: 89%; MS (m/e): 381 (MH⁺). 7.3.1019N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine(R935261) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine was reacted 3,4-ethyelenedioxyaniline to produce N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.85 (s, 1H), 9.40 (s, 1H), 9.01 (s, 1H), 8.07 (d,1H, J =3.5 Hz), 7.97 (s, 1H), 7.86 (s, 1H), 7.65 (d, 1H, J =8.8 Hz),7.47 (dd, 1H, J =2.3 and 8.8 Hz), 7.27 (d, 1H, J =2.3 Hz), 7.07 (dd, 1H,J =2.3 and 8.8 Hz), 6.64 (dd, 1H, J =1.7 and 8.8 Hz), 4.14 (s, 4H).LCMS: ret. time: 15.90 min.; purity: 100%; MS (m/e): 379 (MH⁺). 7.3.10205-Fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-6-yl)-2,4-pyrimidinediamine(R935262) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine was reacted with3-aminophenol to produce5-fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.80 (s, 1H), 10.49 (s, 1H), 8.35 (d, 1H, J =5.3Hz), 8.06 (s, 1H), 7.78 (d, 1H), 7.75 (d, 1H, J =8.8 Hz), 7.42 (dd, 1H,J =1.7 and 8.8 Hz), 6.99-6.97 (m, 2H), 6.80 (s, 1H), 6.52-6.48 (m, 1H).LCMS: ret. time: 13.78 min.; purity: 100%; MS (m/e): 379 (MH⁺). 7.3.1021N2-(3-Chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-2,4-pyrimidinediamine(R935263) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineaminewas reacted with 4-amino-2-chloro-6-methylphenol to produceN2-(3-chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.40 (s, 1H), 9.04 (s, 1H), 8.51 (s, 1H), 8.07 (d,1H, J =3.5 Hz), 7.98 (d, 1H, J =2.3 Hz), 7.67 (s, 1H), 7.53 (s, 1H),7.41-7.36 (m, 1H), 7.20 (s, 1H), 7.10 (d, 1H, J =8.8 Hz), 7.07 (s, 1H),5.24 (s, 2H), 1.98 (s, 3H). LCMS: ret. time: 13.36 min.; purity: 90%; MS(m/e): 439 (MH⁺). 7.3.1022N2-(3-Chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine(R935264) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-6-yl)-4-pyrimidineamine was reacted with4-amino-2-chloro-6-methylphenol to produceN2-(3-chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.62 (s, 1H), 9.19 (s, 1H), 8.61 (s, 1H,), 8.12 (s,1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.67 (d, 1H, J =8.8 Hz), 7.50-7.45 (m,2H), 7.26 (s, 1H), 1.98 (s, 3H). LCMS: ret. time: 13.78 min.; purity:100%; MS (m/e): 385 (MH⁺). 7.3.10235-Fluoro-N4-(indazoline-5-yl)-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine (R935266) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with4-isoporopoxyaniline to produce5-fluoro-N4-(indazoline-5-yl)-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.30 (s, 1H), 9.80 (s, 1H), 8.16 (d, 1H, J =5.3 Hz),8.06 (s, 1H), 7.98 (s, 1H), 7.51 (s, 2H), 7.32 (d, 2H, J =8.8 Hz), 6.79(d, 2H, J=8.8 Hz), 4.51 (sept, 1H, J =5.8 Hz), 1.22 (d, 6H, J =5.8 Hz).LCMS: ret. time: 17.65 min.; purity: 98%; MS (m/e): 379 (MH⁺). 7.3.1024N2-(3,4-Ethyelenedioxyphenyl)-5-fluoro-N4-(indazoline-5-yl)-2,4-pyrimidinediamine(R935267) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with3, 4-ethylenedioxyphenylaniline to produce N2-(3,4-ethyelenedioxyphenyl)-5-fluoro-N4-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.20 (s, 1H), 9.61 (s, 1H), 8.13 (d, 1H, J =5.3 Hz),8.08 (s, 1H), 7.98 (s, 1H), 7.54-7.48 (m, 2H), 7.06 (d, 1H, J =2.3 Hz),6.90 (dd, 1H, J =2.3 and 8.8 Hz), 6.72 (d, 1H, J =8.8 Hz), 4.17 (s, 4H).LCMS: ret. time: 15.16 min.; purity: 100%; MS (m/e): 379 (MH⁺). 7.3.10255-Fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-5-yl)-2,4-pyrimidinediamine(R935268) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with3-aminophenol to produce5-fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.64 (s, 1H), 10.33 (s, 1H), 8.29 (d, 1H, J =5.3Hz), 8.12 (s, 1H), 8.03 (s, 1H), 7.55 (dd, 2H, J =1.7 and 8.8 Hz), 7.00(d, 1H, J =8.8 Hz), 6.90 (d, 1H, J =8.8 Hz), 6.85 (d, 1H, J =1.7 Hz),6.53 (d, 1H, J =8.8 Hz). LCMS: ret. time: 12.80 min.; purity: 98%; MS(m/e): 337 (MH⁺). 7.3.10265-Fluoro-N4-(indazoline-5-yl)-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine (R935269) In like manner tothe preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with3-(methoxycarbonylmethyleneoxy)aniline to produce5-fluoro-N4-(indazoline-5-yl)-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.64 (s, 1H), 9.82 (s, 1H), 8.20 (d, 1H, J =4.6 Hz),8.10 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.57 (m, 2H), 7.13-7.6 (m,3H), 6.56 (d, 1H, J =8.8 Hz), 4.60 (s, 2H), 3.65 (s, 3H). LCMS: ret.time: 15.36 min.; purity: 94%; MS (m/e): 409 (MH⁺). 7.3.10275-Fluoro-N4-(indazoline-5-yl)-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935270) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine was reacted with6-aminoindazoline to produce5-fluoro-N4-(indazoline-5-yl)-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.35 (s, 1H), 9.19 (s, 1H), 8.25 (d, 1H, J =4.1 Hz),8.12 (s, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.64 (d, 1H, J=8.8 Hz), 7.60 (dd, 2H, J =1.7 and 8.9 Hz), 7.51 (d, 1H, J =8.9 Hz),7.21 (dd, 1H, J =1.7 and 8.8 Hz). LCMS: ret. time: 13.45 min.; purity:95%; MS (m/e): 361 (MH⁺). 7.3.10285-Fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R935271) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineaminewas reacted with 3-(N-methylaminocarbonylmethyleneoxy)aniline to produce5-fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.44 (s, 1H), 9.25 (s, 1H), 8.11 (d, 1H, J =3.5 Hz),8.03 (d, 1H, J =2.3 Hz), 7.90 (qt, 1H, J =4.6 Hz), 7.69 (d, 1H, J =1.2Hz), 7.47 -7.42 (m, 1H), 7.33 (m, 1H), 7.26 (dd, 1H, J =1.2 and 8.2 Hz),7.12 (s, 1H), 7.09 (d, 1H, J =1.7 Hz), 6.97 (t, 1H, J =8.2H), 6.40 (dd,1H, J =2.3 and 8.2 Hz), 5.25 (s, 2H), 4.26 (s, 2H), 2.61 (d, 3H, J =4.6Hz). LCMS: ret. time: 15.45 min.; purity: 97%; MS (m/e): 462 (MH⁺).7.3.1029 5-Fluoro-N2-(4-isopropoxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine (R935276) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with4-isopropoxyaniline to produce5-fluoro-N2-(4-isopropoxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ10.69 (s, 1H), 9.03 (s, 1H),8.06 (d, 1H, J =3.5 Hz), 7.30 (d, 2H, J =9.3 Hz), 6.82 (t, 2H, J =2.3Hz), 6.58 (d, 2H, J =9.3 Hz), 6.11 (t, 2H, J =2.3 Hz), 4.41 (sept, 1H, J=5.8 Hz), 1.18 (d, 6H, J =5.8 Hz). LCMS: ret. time: 21.21 min.; purity:90%; MS (m/e): 328 (MH⁺). 7.3.1030 N2-(3,4-Ethylenedioxyphenyl)-5-Fluoro-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine (R935277) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with3, 4-ethylenedioxyaniline to produce N2-(3,4-ethylenedioxyphenyl)-5-Fluoro-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ11.63 (s, 1H), 9.94 (s, 1H),8.23 (d, 1H, J =4.7 Hz), 6.86 (m, 4H), 6.58 (d, 1H, J =8.8 Hz), 6.12 (t,2H, J =2.3 Hz), 4.15 (s, 4H). LCMS: ret. time: 17.36 min.; purity: 96%;MS (m/e): 328 (MH⁺). 7.3.10315-Fluoro-N2-(3-hydroxyphenyl)-N4-(1H-pyrrol-1-yl)- 2,4-pyrimidinediamine(R935278) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with3-aminophenol to produce5-fluoro-N2-(3-hydroxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ10.68 (s, 1H), 9.04 (s, 1H),9.00 (s, 1H), 8.08 (d, 1H, J =4.11 Hz), 7.01 (d, 1H, J =8.2 Hz),6.84-6.75 (m, 4H), 6.22 (dd, 1H, J =1.2 and 8.2 Hz), 6.08 (t, 2H, J =2.3Hz). LCMS: ret. time: 16.24 min.; purity: 94%; MS (m/e): 286 (MH⁺).7.3.10325-Fluoro-N4-(indazoline-5-yl)-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine(R935279) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N4-(indazoline-5-yl)-N2-[3-(-methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N4-(indazoline-5-yl)-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.98 (s, 1H), 9.35 (s, 1H), 9.16 (s, 1H), 8.21 (s,1H), 8.07 (d, 1H, J =3.5 Hz), 7.97 (s, 1H), 7.90 (qt, 1H, J =4.7 Hz),7.59 (dd, 1H, J =8.8 Hz), 7.49 (d, 1H, J =8.8 Hz), 7.32-7.28 (m, 2H),7.03 (t, 1H, J =8.2 Hz), 6.45 (dd, 1H, J =1.7 and 8.2 Hz), 4.31 (s, 2H),2.61 (d, 3H, J =4.7 Hz). LCMS: ret. time: 12.92 min.; purity: 90%; MS(m/e): 408 (MH⁺). 7.3.10335-Fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine (R935280) In like manner tothe preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with3-(methoxycarbonylmethyleneoxy)aniline to produce5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ11.45(s,1H), 9.90 (s, 1H), 8.26 (d, 1H, J =4.7 Hz), 7.07 (d, 1H, J =8.2 Hz),7.68 (d, 1H, J =8.2 Hz), 6.94 (s, 1H), 6.85 (t, 2H, J =2.3 Hz), 6.47(dd, 1H, J =2.3 and 8.2 Hz), 6.12 (t, 2H, J =2.3 Hz), 4.64 (s, 2H), 3.68(s, 3H). LCMS: ret. time: 16.24 min.; purity: 92%; MS (m/e): 358 (MH⁺).7.3.1034 5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine (R935281) In likemanner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,5-fluoro-N2-[3-(-methoxycarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.73 (s, 1H), 9.21 (s, 1H), 8.11 (d, 1H, J =4.1 Hz),7.89 (qt, 1H, J =4.7 Hz), 7.14 (d, 1H, J =8.2 Hz), 7.09 (s, 1H), 6.93(t, 1H, J =8.2 Hz), 6.84 (t, 2H, J =2.3 Hz), 6.40 (dd, 1H, J =2.3 and8.2 Hz), 6.09 (t, 2H, J =2.3 Hz), 4.29 (s, 2H), 2.63 (s, 3H, J =4.7 Hz).LCMS: ret. time: 16.16 min.; purity: 90%; MS (m/e): 357 (MH⁺). 7.3.1035N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]- N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R935286) In likemanner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 6-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]- N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ9.37 (s, 1H), 9.20 (s, 1H), 8.10 (d, 1H, J =3.5 Hz), 8.06 (s, 1H), 7.87(s, 1H), 7.53 (d, 1H, J =8.8 Hz), 7.33-7.21 (m, 3H), 6.77 (d, 1H, J =8.8Hz), 4.34 (t, 2H, J =6.4 Hz), 4.19 (s, 4H), 3.93 (qt, 2H, J =7.0 Hz),2.82 (t, 2H, J =6.4 Hz), 1.04 (t, 3H, J =7.0 Hz). LCMS: ret. time: 24.70min.; purity: 90%; MS (m/e): 479 (MH⁺). 7.3.1036 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935287) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]- N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine was reacted withDIBAL-H to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.35 (s, 1H), 9.19 (s, 1H), 8.09 (d, 1H, J =4.1 Hz),8.01 (s, 1H), 7.85 (s, 1H), 7.53 (d, 1H, J =8.8 Hz), 7.32-7.20 (m, 3H),6.77 (d, 1H, J =8.8 Hz), 4.20 (s, 4H), 3.27 (t, 2H, J =6.4 Hz), 3.27 (t,2H, J =6.4 Hz), 1.84 (q, 2H, J =6.4 Hz). LCMS: ret. time: 24.70 min.;purity: 90%; MS (m/e): 479 (MH⁺). LCMS: ret. time: 22.09 min.; purity:90%; MS (m/e): 437 (MH⁺). 7.3.1037 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine(R935288) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]- N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and Me₂NH.HCl werereacted to provide N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.35 (s, 1H), 9.19 (s, 1H), 8.10 (d, 1H, J =3.5 Hz),8.02 (s, 1H), 7.86 (s, 1H), 7.81 (qt, 1H, J =4.7 Hz), 7.52 (d, 1H, J=8.2 Hz), 7.34-7.22 (m, 3H), 6.77 (d, 1H, J =8.8 Hz), 4.33 (t, 2H, J=6.4 Hz), 4.19 (s, 4H), 2.57 (t, 2H, J =6.4 Hz), 2.48 (d, 3H, J =4.7Hz). LCMS: ret. time: 23.10 min.; purity: 93%; MS (m/e): 464 (MH⁺).7.3.1038 N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(isopropoxyphenyl)-2,4-pyrimidinediamine (R935289) In likemanner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 6-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N4-(isopropoxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ10.74 (s, 1H), 10.55 (s, 1H), 8.35 (d, 1H, J =5.8 Hz), 7.98 (s, 1H),7.77 (s, 1H), 7.66 (d, 1H, J =8.8 Hz), 7.51 (d, 2H, J =8.8 Hz), 7.16(dd, 1H, J =1.2 and 8.8 Hz), 6.85 (d, 2H, J =8.8 Hz), 4.55 (sept, 1H, J=6.4 Hz), 4.31 (t, 2H, J =6.4 Hz), 3.93 (qt, 2H, J =7.0 Hz), 2.80 (t,2H, J =6.4 Hz), 1.22 (d, 6H, J =7.0 Hz), 1.02 (t, 3H, J =7.0 Hz). LCMS:ret. time: 26.84 min.; purity: 96%; MS (m/e): 479 (MH⁺). 7.3.10395-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R935290) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N4-(isopropoxyphenyl)-2,4-pyrimidinediamine was reacted withDIBAL-H to produce5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 9.22 (s, 1H), 8.08 (d, 1H, J =4.1 Hz),7.98 (s, 1H), 7.85 (s, 1H), 7.62 (dd, 2H, J =3.5 and 8.8 Hz), 7.52 (d,1H, J =8.8 Hz), 7.27 (d, 1H, J =8.8 Hz), 6.86 (d, 2H, J =8.8 Hz), 4.55(sept, 1H, J =7.0 Hz), 4.49 (t, 1H, J =5.3 Hz), 4.14 (t, 2H, J =6.4 Hz),3.26 (t, 2H, J =6.4 Hz), 1.84 (q, 2H, J =6.4 Hz), 1.24 (d, 6H, J =7.0Hz). LCMS: ret. time: 24.13 min.; purity: 97%; MS (m/e): 437 (MH⁺).7.3.10405-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylamino)carbonyl]ethyl-indazoline-6-yl]-2,4-pyrimidinediamine(R935291) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N4-(isopropoxyphenyl)-2,4-pyrimidinediamine and Me₂NH.HCl werereacted to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylamino)carbonyl]ethyl-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.32(s, 1H), 9.24 (s, 1H), 8.10 (d, 1H, J =3.5 Hz),7.99 (s, 1H), 7.85 (s, 1H), 7.80 (qt, 1H, J =4.7 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.52 (d, 1H, J =8.8 Hz), 7.28 (d, 1H, J =8.8 Hz), 6.84 (d, 2H,J =8.8 Hz), 4.54 (sept, 1H, J =5.8 Hz), 4.30 (t, 2H, J =6.4 Hz), 2.55(t, 2H, 7.4 Hz), 2.48 (d, 3H, J =4.7 Hz), 1.24 (d, 6H, J =6H). LCMS:ret. time: 23.68 min.; purity: 95%; MS (m/e): 464 (MH⁺). 7.3.1041N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R935292) In likemanner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ10.35 (s, 1H), 10.21 (s, 1H), 8.29 (d, 1H, J =5.3 Hz), 7.96 (s, 1H),7.90 (s, 1H), 7.63 (d, 1H, J =8.8 Hz), 7.20-7.06 (m, 4H), 6.58 (d, 1H, J=8.2 Hz), 4.33 (t, 2H, J =6.4 Hz), 3.94 (qt, 2H, J =7.0 Hz), 2.82 (t,2H, J =6.4 Hz), 1.03 (t, 3H, J =7.0 Hz). LCMS: ret. time: 22.73 min.;purity: 94%; MS (m/e): 437 (MH⁺). 7.3.10425-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine(R935293) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine was reacted withDIBAL-H to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.38 (s, 1H), 9.35 (s, 1H), 9.26 (s, 1H), 8.13 (d,1H, J =4.1 Hz), 8.05 (s, 1H), 7.85 (s, 1H), 7.52 (d, 1H, J =8.2 Hz),7.28 (d, 2H, J =8.8 Hz), 7.12 (d, 1H, J =1.7 Hz), 7.08 (t, 1H, J =8.2Hz), 6.49 (d, 1H, J =8.2 Hz), 4.15 (t, 2H, J =7.0 Hz), 3.26 (t, 2H, J=6.4 Hz), 1.85 (q, 2H, J =6.4 Hz). LCMS: ret. time: 24.70 min.; purity:90%; MS (m/e): 479 (MH⁺). LCMS: ret. time: 20.37 min.; purity: 98%; MS(m/e): 395 (MH⁺). 7.3.10435-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine(R935294) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine and Me₂NH.HCl werereacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.36 (s, 1H), 9.33 (s, 1H), 9.25 (s, 1H), 8.14 (d,1H, J =3.5 Hz), 8.05 (s, 1H), 7.85 (s, 1H), 7.78 (qt, 1H, J =4.7 Hz),7.52 (d, 1H, J =8.8 Hz), 7.30 (d, 2H, J =8.8 Hz), 7.11 (d, 1H, J =2.3Hz), 7.07 (t, 1H, J =8.2 Hz), 6.47 (d, 1H, J =8.2 Hz), 4.32 (t, 2H, J=6.4 Hz), 2.57 (t, 2H, J =6.4 Hz), 2.48 (d, 3H, J =4.7 Hz). LCMS: ret.time: 20.18 min.; purity: 93%; MS (m/e): 422 (MH⁺). 7.3.1044N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R935295) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(2-methoxycarbonylbenzofur-5-yl)-4-pyrimidineaminewas reacted with 6-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediaminePurification of the crude gave two products.N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R935295): ¹H NMR (DMSO-d₆): δ9.54 (s, 1H), 9.41 (s, 1H), 8.21 (app d,1H, J =1.7 Hz), 8.17 (d, 1H, J =3.5 Hz), 8.01 (s, 1H), 7.86 (s, 1H),7.83-7.80 (m 2H), 7.68 (d, 1H, J =8.8 Hz), 7.59 (s, 1H), 7.52 (d, 1H, J=8.2 Hz), 7.25 (d, 1H, J =8.2 Hz), 4.12 (t, 2H, J =6.4 Hz), 3.91 (qt,2H, J =7.0 Hz), 3.88 (s, 3H), 2.72 (t, 2H, J =6.4 Hz), 1.02 (t, 3H, J=7.0 Hz). LCMS: ret. time: 25.67 min.; purity: 91%; MS (m/e): 519 (MH⁺)and N4-[1-(2-carboxyethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine(R935296) ¹H NMR (DMSO-d₆): δ9.54 (s, 1H), 9.39 (s, 1H), 8.23 (app d,1H, J =1.7 Hz), 8.17 (d, 1H, J =3.5 Hz), 8.00 (s, 1H), 7.86 (s, 1H),7.83-7.80 (m 2H), 7.68 (d, 1H, J =8.8 Hz), 7.58 (s, 1H), 7.52 (d, 1H, J=8.2 Hz), 7.28 (d, 1H, J =8.2 Hz), 4.13 (t, 2H, J =6.4 Hz), 3.88 (s,3H), 2.67 (t, 2H, J =6.4 Hz). LCMS: ret. time: 23.28 min.; purity: 91%;MS (m/e): 491 (MH⁺). 7.3.10455-Fluoro-N4-[2-(N-methylaminocarbonyl)benzofuran-5-yl]-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine(R935297) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine andMe₂NH.HCl were reacted to provide5-fluoro-N4-[2-(N-methylaminocarbonyl)benzofuran-5-yl]-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.00 (s, 1H), 9.90 (s, 1H), 8.70 (qt, 1H, J =4.7Hz), 8.24 (d, 1H, J =4.1 Hz), 8.12 (d, 1H, J =1.7 Hz), 7.911 (s, 1H),7.86 (s, 1H), 7.81 (qt, 1H, J =4.7 Hz), 7.71 (d, 2H, J =1.7 and 8.8 Hz),7.57 (dd, 1H, J =3.5 and 8.8 Hz), 7.35 (s, 1H), 7.26 (dd, 1H, J =3.5 and8.8 Hz), 4.19 (t, 2H, J =7.0 Hz), 2.53 (t, 2H, J =7.0 Hz), 2.47 (d, 6H,J =4.7 Hz). LCMS: ret. time: 20.18 min.; purity: 89%; MS (m/e): 503(MH⁺). 7.3.10465-Fluoro-N4-(4-isopropoxyphenyl)-N2-(2-methyl-indazoline-5-yl)-2,4-pyrimidinediamine(R935298) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine and5-amino-2-methylindazoline were reacted to give5-fluoro-N4-(4-isopropoxyphenyl)-N2-(2-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.15 (s, 1H), 9.03 (s, 1H), 8.03-8.00 (m, 3H), 7.60(dd, 2H, J =4.1 and 8.8 Hz), 7.42 (d, 1H, J =9.3 Hz), 7.31 (d, 1H, J=9.3 Hz), 6.86 (d, 2H, J =8.8 Hz), 4.57 (sept, 1H, J =6.4 Hz), 4.08 (s,3H), 1.26 (d, 6H, J =6.4 Hz), LCMS: ret. time: 23.89 min.; purity: 98%;MS (m/e): 393 (MH⁺). 7.3.10475-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine(R935299) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with5-amino-2-methylindazoline to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.35 (s, 1H), 10.30 (s, 1H), 9.62 (br s, 1H), 8.22(d, 1H, J =5.3 Hz), 8.13 (s, 1H), 7.85 (s, 1H), 7.49 (d, 1H, J =8.8 Hz),7.17 (dd, 1H, J =1.7 and 9.3 Hz), 7.08 (d, 2H, J =5.3 Hz), 7.03 (s, 1H),6.64-6.60 (m, 1H), 4.09 (s, 3H). LCMS: ret. time: 20.01 min.; purity:97%; MS (m/e): 351 (MH⁺). 7.3.1048 N4-(3,4-Ethyelenedioxyphenyl)-5-fluoro-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine(R935300) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5- fluoro-4-pyrimidineamine wasreacted with 5-amino-2-methylindazoline to produce N4-(3,4-ethyelenedioxyphenyl)-5-fluoro-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.64 (s, 1H), 10.62 (s, 1H), 8.22 (d, 1H, J =5.3Hz), 8.21 (s, 1H), 7.77 (s, 1H), 7.58 (d, 1H, J =9.3 Hz), 7.23-7.19 (m,2H), 7.10 (dd, 1H, J =2.3 and 8.8 Hz), 6.78 (d, 1H, J =8.8 Hz), 4.21 (s,3H), 4.15 (s, 4H). LCMS: ret. time: 21.77 min.; purity: 92%; MS (m/e):393 (MH⁺). 7.3.1049 N2-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-N4-(3, 4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R935301)In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]- N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ9.15 (s, 1H), 9.13 (s, 1H), 8.10, (s, 1H), 8.04 (d, 1H, J =3.5 Hz),7.83 (s, 1H), 7.50 (s, 2H), 7.30 (d, 1H, J =2.3 and 8.8 Hz), 6.79 (d,1H, J =8.8 Hz), 4.55 (t, 2H, J =6.4 Hz), 4.22 (s, 4H), 3.97 (qt, 2H, J=7.0 Hz), 2.88 (t, 2H, J =6.4 Hz), 1.06 (t, 3H, J =7.0 Hz). LCMS: ret.time: 25.19 min.; purity: 93%; MS (m/e): 479 (MH⁺). 7.3.1050 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935302) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]- N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine was reacted withDIBAL-H to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.14 (s, 1H), 9.13 (s, 1H), 8.09 (s, 1H), 8.03 (d,1H, J =4.1 Hz), 7.82 (s, 1H), 7.48 (s, 2H), 7.30 (d, 1H, J =2.3 Hz),7.18 (dd, 1H, J =2.3 and 8.8 Hz), 6.78 (d, 1H, J =8.8 Hz), 4.59 (t, 1H,J =6.4 Hz), 4.37 (t, 2H, J =6.4 Hz), 4.22 (s, 4H), 3.34 (t, 2H, J =6.4Hz), 1.84 (q, 2H, J =6.4 Hz). LCMS: ret. time: 22.33 min.; purity: 100%;MS (m/e): 437 (MH⁺). 7.3.1051N4-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R935303) In likemanner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ10.50 (s, 1H), 10.46 (s, 1H), 9.62 (br s 1H), 8.28 (d, 1H, J =5.8 Hz),7.96 (s, 2H), 7.65 (d, 1H, J =8.8 Hz), 7.36 (dd, 1H, J =1.7 and 8.8 Hz),7.15-7.08 (m, 3H), 6.67-6.64 (m, 1H), 4.59 (t, 2H, J =6.4 Hz), 3.97 (qt,2H, J =7.0 Hz), 2.89 (t, 2H, J =6.4 Hz), 1.06 (t, 3H, J =7.0 Hz). LCMS:ret. time: 23.68 min.; purity: 97%; MS (m/e): 437 (MH⁺). 7.3.10525-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935304) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine was reacted withDIBAL-H to produce5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.39 (s, 1H), 9.18 (s, 1H), 9.15 (s, 1H), 8.20 (s,1H), 8.07 (d, 1H, J =4.1 Hz), 7.84 (s, 1H), 7.46 (s, 2H), 7.24 (d, 1H, J=8.2 Hz), 7.11-7.06 (m, 2H), 6.53 (d, 1H, J =8.8 Hz), 4.56 (t, 1H, J=4.7 Hz), 4.37 (t, 2H, J =6.4 Hz), 3.34 (t, 2H, J =6.4 Hz), 1.92 (q, 2H,J =6.4 Hz). LCMS: ret. time: 24.70 min.; purity: 90%; MS (m/e): 479(MH⁺). LCMS: ret. time: 20.89 min.; purity: 98%; MS (m/e): 395 (MH⁺).7.3.10535-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine(R935305) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine and Me₂NH.HCl werereacted to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.39 (s, 1H), 9.18 (s, 1H), 9.15 (s, 1H), 8.19 (s,1H), 8.06 (d, 1H, J =3.5 Hz), 7.84 (s, 1H), 7.82 (qt. 1H, J =4.7 Hz),7.46 (t, 2H, J =8.2 Hz), 7.25 (d, 1H, J =8.2 Hz), 7.11 (d, 1H, J =8.2Hz), 7.10 (d, 1H, J =8.2 Hz), 6.53 (t, 1H, J =8.2 Hz), 4.51 (t, 2H, J=7.0 Hz), 2.61 (t, 2H, J =7.0 Hz), 2.49 (d, 3H, J =4.7 Hz). LCMS: ret.time: 20.66 min.; purity: 95%; MS (m/e): 422 (MH⁺). 7.3.1054N4-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine (R935306) In likemanner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ10.48 (s, 1H), 10.41 (s, 1H), 8.25 (d, 1H, J =5.8 Hz), 7.93(s, 1H), 7.84 (s, 1H), 7.66 (d, 1H, J =8.8 Hz), 7.49 (d, 2H, J =8.8 Hz),7.36 (dd, 1H, J =2.3 and 8.8 Hz), 6.86 (d, 2H, J =8.8 Hz), 4.59 (t, 2H,J =6.4 Hz), 4.57 (sept, 1H, J =7.0 Hz), 3.96 (qt, 2H, J =7.0 Hz), 2.89(t, 2H, J =6.4 Hz), 1.23 (d, 6H, J =7.0 Hz), 1.05 (t, 3H, J =7.0 Hz).LCMS: ret. time: 27.39 min.; purity: 98%; MS (m/e): 479 (MH⁺). 7.3.10555-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R935307) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine was reacted withDIBAL-H to produce5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.16 (s, 1H), 9.10 (s, 1H), 8.09 (s, 1H), 8.03 (d,1H, J =4.1 Hz), 7.79 (s, 1H), 7.57 (d, 2H, J =8.8 Hz), 7.46 (t, 2H),6.87 (d, 2H, J =8.8 Hz), 4.60-4.52 (m, 2H), 4.37 (t, 2H, J =6.4 Hz),3.34 (t, 2H, J =6.4 Hz), 1.84 (q, 2H, J =6.4 Hz), 1.24 (d, 6H, J =7.0Hz). LCMS: ret. time: 23.71 min.; purity: 98%; MS (m/e): 437 (MH⁺).7.3.1056 5-Fluoro-N4-(2-hydroxymethylbenzofur-5-yl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]- 2,4-pyrimidinediamine (R935308)In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine wasreacted with DIBAL-H to produce5-fluoro-N4-(2-hydroxymethylbenzofur-5-yl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]- 2,4-pyrimidinediamine. ¹H NMR(DMSO-d₆): δ9.35 (s, 1H), 9.33 (s, 1H), 8.12 (d, 1H, J =3.5 Hz), 7.99(d, 1H, J =1.7 Hz), 7.95 (s, 1H), 7.84 (s, 1H), 7.55-7.49 (m, 3H), 7.28(d, 1H, J =8.8 Hz), 6.62 (s, 1H), 5.46 (t, 1H, J =5.8 Hz), 4.55 (d, 2H,J =5.8 Hz), 4.45 (t, 1H, J =4.7 Hz), 3.96 (t, 2H, J =6.4 Hz), 3.20 (t,2H, J =6.4 Hz), 1.76 (q, 2H, J =6.4 Hz). LCMS: ret. time: 20.86 min.;purity: 99%; MS (m/e): 449 (MH⁺). 7.3.1057 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine(R935309) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]- N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and Me₂NH.HCl werereacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.12 (s, 1H), 9.11 (s, 1H), 8.09 (s, 1H), 8.03 (d,1H, J =3.5 Hz), 7.82 (s, 2H), 7.47 (s, 2H), 7.32-7.30 (m, 1H), 7.22-7.17(m, 1H), 6.80 (d, 1H, J =8.8 Hz), 4.51 (t, 2H, J =7.0 Hz), 4.22 (s, 4H),2.62 (t, 2H, J =7.0 Hz), 2.49 (d, 3H, J =4.7 Hz). LCMS: ret. time: 18.67min.; purity: 100%; MS (m/e): 464 (MH⁺). 7.3.10585-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine(R935310) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine and Me₂NH.HClwere reacted to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.18 (s, 1H), 9.09 (s, 1H), 8.08 (s, 1H), 8.02 (d,1H, J =4.1 Hz), 7.82 (qt, 1H, J =4.7 Hz), 7.79 (s, 1H), 7.57 (d, 2H, J=8.8 Hz), 7.45 (d, 2H, J =8.8 Hz), 6.87 (d, 2H, J =8.8 Hz), 4.57 (q, 2H,J =5.8 Hz), 4.51 (t, 2H, J =7.0 Hz), 2.61 (t, 2H, J =7.0 Hz), 2.47 (d,3H, J =4.7 Hz), 1.26 (d, 6H, J =5.8 Hz). LCMS: ret. time: 17.14 min.;purity: 99%; MS (m/e): 464 (MH⁺). 7.3.1059 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine (R935320) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 6-amino-1-(2-methoxy-3-carbomethoxybenzyl)indazoline toprovide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.36 (s, 1H), 9.18 (s, 1H), 8.08 (d, 1H, J =3.5 Hz),8.04 (s, 1H), 7.56 (d, 1H, J =8.2 Hz), 7.45 (d, 1H, J =1.8 Hz),7.43-7.38 (m, 1H), 7.36-7.34 (m, 1H), 7.30 (dd, 1H, J =1.7 and 8.8 Hz),7.20 (dd, 1H, J =2.3 and 8.8 Hz), 6.75 (d, 1H, J =8.8 Hz), 6.68 (d, 1H,J =8.2 Hz), 6.48 (dd, 1H, J =1.7 and 8.2 Hz), 5.39 (s, 2H), 4.16 (s,4H), 3.83 (s, 3H), 3.79 (s, 3H). LCMS: ret. time: 29.92 min.; purity:80%; MS (m/e): 557 (MH⁺). 7.3.10605-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine (R935321) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-1-(2-methoxy-3-carbomethoxybenzyl)indazoline to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.37 (s, 1H), 9.31(s, 1H), 9.23 (s, 1H), 8.11 (d, 1H,J =3.5 Hz), 8.08 (s, 1H), 7.93 (s, 1H), 7.57 (d, 1H, J =8.8 Hz), 7.45(d, 1H, J =1.7 Hz), 7.40 (dd, 1H, J =1.7 and 8.8 Hz), 7.33-7.27 (, 2H),7.13 (t, 1H, J =1.7 HZ), 7.03 (t, 2H, J =8.2 Hz), 6.67 (d, 1H, J =8.2Hz), 6.45 (dd, 1H, J =1.7 and 8.2 Hz), 5.37 (s, 2H), 3.83 (s, 3H), 3.79(s, 3H). LCMS: ret. time: 28.80 min.; purity: 92%; MS (m/e): 515 (MH⁺).7.3.10615-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine(R935322) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.60 (s, 2H), 8.11 (d, 1H, J =4.1 Hz), 8.00-7.92 (m,3H), 7.61-7.53 (m, 4H), 7.47-7.24 (m, 5H), 6.81 (d, 2H, J =8.8 Hz), 6.68(d, 1H, J =8.2 Hz), 5.34 (s, 2H), 4.48 (sept, 1H, J =5.9 Hz), 3.82 (s,3H), 2.55 (s, 3H), 1.21 (d, 6H, J =5.9 Hz). LCMS: ret. time: 30.57 min.;purity: 95%; MS (m/e): 696 (MH⁺). 7.3.1062 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine(R935323) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine.. ¹H NMR (DMSO-d₆): δ9.53 (s, 1H), 9.41 (s, 1H), 8.05 (d, 1H, J =4.1Hz), 7.96-7.90 (m, 3H), 7.55 (d, 1H, J =8.8 Hz), 7.49 (dd, 1H, J =7.6Hz), 7.42-7.20 (m, 6H), 7.14-7.10 (m, 1H), 6.69 (d, 1H, J =8.2 Hz), 6.60(d, 1H, J =8.8 Hz), 5.33 (s, 2H), 4.10 (s, 4H), 3.77 (s, 3H), 2.50 (s,3H). LCMS: ret. time: 32.11 min.; purity: 93%; MS (m/e): 696 (MH⁺).7.3.10635-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine(R935324) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.64 (s, 1H), 9.56 (s, 1H), 8.15 (d, 1H, J =4.1 Hz),8.00 (s, 1H), 7.97 (d, 2H, J =8.8 Hz), 7.60 (d, 1H, J =8.8 Hz), 7.53 (d,1H, J =1.2 and 8.8 Hz), 7.47-7.23 (m, 6H), 7.11 (t, 1H, J =1.7 Hz), 7.03(t, 1H, J =8.2 Hz), 6.62 (d, 1H, J =8.2 Hz), 6.48 (dd, 1H, J =1.7 and8.2 Hz), 5.36 (s, 2H), 3.82 (s, 3H), 2.55 (s, 3H). LCMS: ret. time:29.79 min.; purity: 92%; MS (m/e): 654 (MH⁺). 7.3.1064 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine (R935336) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 6-amino-2-(2-methoxy-3-carbomethoxybenzyl)indazoline toprovide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.16 (s, 1H), 9.14 (s, 1H), 8.24 (s, 1H), 8.06 (s,1h), 8.04 (d, 1H, J =3.5 Hz), 7.51 (d, 2H, J =7.7 Hz), 7.49 (s, 1H),7.29-7.26 (m, 2H), 7.19 (d, 1H, J =7.7 Hz), 6.92 (d, 1H, J =8.8 Hz),6.76 (d, 1H, J =8.2 Hz), 5.58 (s, 2H), 4.22 (s, 4H), 3.92 (s, 3H), 3.82(s, 3H). LCMS: ret. time: 10.91 min.; purity: 91%; MS (m/e): 557 (MH⁺).7.3.10655-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine (R935337) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with6-amino-2-(2-methoxy-3-carbomethoxybenzyl)indazoline to provide5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 9.17 (s, 1H), 9.15 (s, 1H), 8.26 (s,1H), 8.09 (d, 1H, J =5.8 Hz), 8.08 (s, 1H), 7.52 (app t, 3H, J =7.6 Hz),7.42 (d, 1H, J =8.2 Hz), 7.23 (d, 1H, J =8.2 Hz), 7.08 (app s,1H), 7.03(d, 1H, J =8.2 Hz), 6.93 (d, 1H, J =7.6 Hz), 6.43 (d, 1H, J =8.2 Hz),5.57 (s,2H), 3.90 (s, 3H), 3.82 (s, 3H). LCMS: ret. time: 10.51 min.;purity: 93%; MS (m/e): 515 (MH⁺). 7.3.10665-Fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine (R935338) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reactedwith 6-amino-2-(2-methoxy-4-carbomethoxybenzyl)indazoline to provide5-fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.20 (s, 1H), 9.16 (s, 1H), 8.26 (s, 1H), 8.16 (s,1H), 8.06 (d, 1H, J =3.5 Hz), 7.66 (d, 2H, J =8.8 Hz), 7.52-7.48 (m,3H), 7.15 (d, 1H, J =8.2 Hz), 6.86 (d, 2H, J =8.8 Hz), 6.81 (d, 1H, J=8.8 Hz), 5.56 (s, 2H), 4.46 (sept, 1H, J =5.9 Hz), 3.91 (s, 3H), 3.82(s, 3H), 1.17 (d, 6H, J =5.9 Hz). LCMS: ret. time: 11.94 min.; purity:90%; MS (m/e): 557 (MH⁺). 7.3.1067 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine(R935339) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with5-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine.. ¹H NMR (DMSO-d₆): δ9.57 (br s, 2H), 8.08 (d, 1H, J =3.5 Hz), 8.01 (s,1H), 7.99 (d, 1H, J =1.0 Hz), 7.95 (s, 1H), 7.59-7.32 (m, 3H), 7.45-7.32(m, 4H), 7.27-7.24 (m, 1H), 7.17-7.12 (m, 1H), 6.74 (d, 1H, J =8.7 Hz),6.65 (d, 1H, J =8.7 Hz), 5.58 (s, 2H), 4.15 (s, 4H), 3.88 (s, 3H), 2.56(s, 3H). LCMS: ret. time: 11.33 min.; purity: 98%; MS (m/e): 696 (MH⁺).7.3.10685-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine(R935340) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with5-amino-1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline toprovide5-fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.57 (s, 1H), 9.48 (s, 1H), 8.13 (app s, 2H), 8.00(d, 1H, J =8.2 Hz), 7.94 (s, 1H), 7.59-7.32 (m, 7H), 7.18 (d, 1H, J =8.2Hz), 7.06 (app t, 3H, J =8.8 Hz), 6.64 (d, 1H, J =8.2 Hz), 6.55 (d, 1H,J =8.2 Hz), 5.57 (s, 2H), 3.88 (s, 3H), 2.56 (s, 3H). LCMS: ret. time:10.16 min.; purity: 97%; MS (m/e): 654 (MH⁺). 7.3.1069N4-(4-Chlorophenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine(R935351) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chlorophenyl)-5-fluoro 4-pyrimidineamine and1-methyl-5-aminoindazoline were reacted to giveN4-(4-chlorophenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.86 (s, 1H), 9.61 (s, 1H), 8.17 (d, 1H, J =4.1 Hz),8.00 (s, 1H), 7.88 (s, 1H), 7.78 (d, 2H, J =8.8 Hz), 7.57 (d, 1H, J =8.8Hz), 7.43 (d, 1H, J =8.8 Hz), 7.34 (d, 2H, J =8.8 Hz), 4.00 (s, 3H).LCMS: ret. time: 10.64 min.; purity: 94%; MS (m/e): 369 (MH⁺). 7.3.1070N4-(4-Chlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935352) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chlorophenyl)-5-fluoro 4-pyrimidineamime and6-aminoindazoline were reacted to giveN4-(4-chlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.18 (s, 1H), 10.02 (s, 1H), 8.26 (d, 1H, J =4.1Hz), 7.98 (s, 1H), 7.84 (d, 1H, J =8.8 Hz), 7.82 (d, 2H, J =8.8 Hz),7.65 (d, 1H, J =8.8 Hz), 7.35 (d, 2H, J =8.8 Hz), 7.19 (d, 1H, J =8.8Hz). LCMS: ret. time: 10.80 min.; purity: 90%; MS (m/e): 355 (MH⁺).7.3.1071N4-(4-Chlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935353) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine was reacted with5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-(4-chlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.37 (s, 1H), 10.17 (s, 1H), 8.26 (d, 1H, J =5.3Hz), 7.96 (s, 1H), 7.88 (s, 1H), 7.33-7.66 (m, 3H), 7.40 (d, 1H, J =8.8Hz), 7.35 (d, 2H, J =8.8 Hz), 4.61 (t, 2H, J =6.4 Hz), 3.97 (qt, 2H, J=7.0 Hz), 2.91 (t, 2H, J =6.4 Hz), 1.05 (t, 3H, J =7.0 Hz). LCMS: ret.time: 11.85 min.; purity: 95%; MS (m/e): 455 (MH⁺). 7.3.1072N4-(3-Chloro-4-trifluoromethoxy-phenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935354) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-trifluoromethoxy-phenyl)-5-fluoro-4-pyrimidineaminewas reacted with 5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN4-(3-chloro-4-trifluoromethoxy-phenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.63 (s, 1H), 9.30 (s, 1H), 8.17 (d, 1H, J =3.5 Hz),8.10 (t, 1H, J =2.3 Hz), 8.01 (s, 1H), 7.87 (s, 1H), 7.86 (d, 1H, J =8.2Hz), 7.57 (d, 1H, J =9.4 Hz), 7.47 (t, 2H, J =10.0 Hz), 4.56 (t, 2H, J=6.9 Hz), 3.97 (qt, 2H, J =7.0 Hz), 2.88 (t, 2H, J =6.9 Hz), 1.06 (t,3H, J =7.0 Hz). LCMS: ret. time: 14.4 min.; purity: 95%; MS (m/e): 539(MH⁺). 7.3.1073 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935355) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-dichlorophenyl)-5-fluoro 4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to give N4-(3,4-dichlorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.63 (s, 1H), 9.35 (s, 1H), 8.17 (d, 1H, J =3.5 Hz),8.08 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.79 (d, 1H, J =8.8 Hz), 7.53(d, 2H, J =8.2 Hz), 7.47 (d, 1H, J =8.2 Hz), 3.99 (s, 3H). LCMS: ret.time: 12.30 min.; purity: 98%; MS (m/e): 404 (MH⁺). 7.3.10745-Fluoro-N2-(1-methylindazoline-5-yl)-N4-(3-trifluoromethoxypheny)-2,4-pyrimidinediamine(R935356) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-trifluoromethoxyphenyl)-4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to give5-fluoro-N2-(1-methylindazoline-5-yl)-N4-(3-trifluoromethoxypheny)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.37 (s, 1H), 10.17 (s, 1H), 8.25 (d, 1H, J =4.1Hz), 7.92 (s, 2H), 7.84 (d, 1H, J=9.4 Hz), 7.75 (s, 1H), 7.59 (d, 1H, J=8.8 Hz), 7.45 (d, 1H, J=9.4 Hz), 7.38 (d, 1H, J =9.4 Hz), 7.08 (d, 1H,J =8.8 Hz), 3.99 (s, 3H). LCMS: ret. time: 12.13 min.; purity: 94%; MS(m/e): 419 (MH⁺). 7.3.1075 N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935357) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to give N4-(3,4-difluoromethylendioxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.84 (s, 1H), 9.54 (s, 1H), 8.16 (d, 1H, J =4.1 Hz),8.00 (s, 2H), 7.87 (s, 1H), 7.55-7.32 (m, 4H), 3.99 (s, 3H). LCMS: ret.time: 11.26 min.; purity: 96%; MS (m/e): 415 (MH⁺). 7.3.1076 N4-(3,4-Difluorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935358) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-difluorophenyl)-5-fluoro-4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to give N4-(3,4-difluorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.50 (s, 1H), 9.27 (s, 1H), 8.13 (d, 1H, J =4.1 Hz),8.08 (app s, 2H), 7.85 (s, 1H), 7.50 (app s, 3H), 7.37 (q, 1H, J =9.4Hz), 3.99 (s, 3H). LCMS: ret. time: 10.42 min.; purity: 90%; MS (m/e):371 (MH⁺). 7.3.1077N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935359) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamimeand 1-methyl-5-aminoindazoline were reacted to giveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.79 (s, 1H), 9.45 (s, 1H), 8.19 (d, 1H, J =4.1 Hz),8.09 (t, 1H, J =2.8 Hz), 8.00 (s, 1H), 7.85-7.81 (m, 2H), 7.51 (d, 1H, J=8.8 Hz), 7.48-7.44 (m, 2H), 3.99 (s, 3H). LCMS: ret. time: 13.14 min.;purity: 92%; MS (m/e): 453 (MH⁺). 7.3.1078N2-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R935360) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-trifluoromethoxyphenyl)-4-pyrimidineamine wasreacted with 5-amino-1-(2-ethoxycarbonylethyl)indazoline to provideN2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.55 (s, 1H), 9.26 (s, 1H), 8.15 (d, 1H, J =3.5 Hz),8.05 (s, 1H), 7.95 (d, 1H, J =8.2 Hz), 7.88 (s, 1H), 7.78 (s, 1H), 7.58(dd, 1H, J =8.8 and 7.4 Hz), 7.39 (t, 1H, J =8.2 Hz), 7.01 (d, 1H, J=8.8 Hz), 4.56 (t, 2H, J =7.0 Hz), 3.97 (q, 4H, J =7.0 Hz), 2.88 (t, 2H,J =7.0 Hz), 1.06 (t, 3H, J =7.0 Hz). LCMS: ret. time: 13.22 min.;purity: 95%; MS (m/e): 505 (MH⁺). 7.3.10795-Fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine (R935361) In likemanner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provide5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆):δ9.55 (s, 1H), 9.25 (s, 1H), 8.15 (d, 1H, J =3.5 Hz), 8.04 (s, 1H), 7.96(d, 1H, J =8.2 Hz), 7.87 (s, 1H), 7.83 (qt, 1H, J =4.9 Hz), 7.70 (s,1H), 7.49 (dd, 2H, J =8.2 and 9.4 Hz), 7.40 (d, 1H, J =8.8 Hz), 7.01 (d,1H, J =8.8 Hz), 4.52 (t, 2H, J =7.0 Hz), 2.63 (t, 2H, J =7.0 Hz), 2.49(d, 3H, J =4.7 Hz). LCMS: ret. time: 10.00 min.; purity: 100%; MS (m/e):490 (MH⁺). 7.3.10805-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R935362) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine was reactedwith DIBAL-H to produce5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.55 (s, 1H), 9.24 (s, 1H), 8.15 (d, 1H, J =2.9 Hz),8.05 (s, 1H), 7.92 (d, 1H, J =7.6 Hz), 7.87 (s, 1H), 7.78 (s, 1H), 7.50(s, 2H), 7.39 (t, 1H, J =8.2 Hz), 7.01 (d, 1H, J =7.6 Hz), 4.56 (t, 1H,J =5.2 Hz), 4.38 (t, 2H, J =7.0 Hz), 3.35 (dd, 2H, J =5.2 and 7.0 Hz),1.84 (qt, 2H, J =7.0 Hz). LCMS: ret. time: 10.42 min.; purity: 97%; MS(m/e): 463 (MH⁺). 7.3.10815-Fluoro-N2-(indazoline-6-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R935363) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-trifluoromethoxyphenyl)-4-pyrimidineamine and6-aminoindazoline were reacted to give5-fluoro-N2-(indazoline-6-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.72(s, 1H), 9.60 (s, 1H), 9.42 (s, 1H), 8.21 (d,1H, J =3.5 Hz), 8.06 (br s, 2H), 7.89 (s, 1H), 7.83 (s, 1H), 7.57 (d,1H, J =8.8 Hz), 7.42 (t, 1H, J =8.2 Hz), 7.27 (d, 1H, J =8.8 Hz), 7.00(d, 1H, J =8.2 Hz). LCMS: ret. time: 12.17 min.; purity: 97%; MS (m/e):405 (MH⁺). 7.3.1082 5-Fluoro-N2-(indazoline-5-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine (R935364) In like manner to thepreparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(3-trifluoromethoxyphenyl)-4-pyrimidineamime and5-aminoindazoline were reacted to give5-fluoro-N2-(indazoline-5-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.85 (s, 1H), 9.54 (s, 1H), 9.23 (s, 1H), 8.15 (d,1H, J =3.5 Hz), 8.05 (s, 1H), 7.93 (d, 1H, J =8.2 Hz), 7.89 (s, 1H),7.78 (s, 1H), 7.48-7.35 (m, 3H), 7.01 (d, 1H, J =8.2 Hz). LCMS: ret.time: 10.44 min.; purity: 98%; MS (m/e): 405 (MH⁺). 7.3.1083N4-(4-Chlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935365) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chlorophenyl)-5-fluoro 4-pyrimidineamime and5-aminoindazoline were reacted to giveN4-(4-chlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.85 (s, 1H), 9.43 (s, 1H), 9.19 (s, 1H), 8.11 (d,1H, J =3.5 Hz), 8.08 (s, 1H), 7.87 (s, 1H), 7.82 (dd, 2H, J =3.0 and 8.8Hz), 7.42 (dd, 2H, J =3.0 and 8.8 Hz), 7.31 (d, 2H, J =8.8 Hz). LCMS:ret. time: 9.07 min.; purity: 91%; MS (m/e): 355 (MH⁺). 7.3.1084N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935366) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamimeand 5-aminoindazoline were reacted to giveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.90 (s, 1H), 9.45 (s, 1H), 9.27 (s, 1H), 8.15 (d,1H, J =3.5 Hz), 8.11 (t, 1H, J =3.0 Hz), 8.02 (s, 1H), 7.87 (s, 1H),7.84 (d, 1H, J =8.8 Hz), 7.47 (d, 2H, J =8.8 Hz), 7.44 (d, 1H, J =8.8Hz). LCMS: ret. time: 11.65 min.; purity: 98%; MS (m/e): 439 (MH⁺).7.3.10855-Fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (R935367) In like manner tothe preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamineand 3, 4,5-trimethoxyaniline were reacted by microwave heating at 180°C. Upon concentration of the ethanol and addition of 2N HCl provided5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine as fine flakes of the solid.¹H NMR (DMSO-d₆): δ9.59 (s, 1H), 9.25 (s, 1H), 8.09 (d, 1H, J =3.5 Hz),8.01 (dd, 2H, J =5.3 and 1.2 Hz), 7.39 (dd, 2H, J =3.1 and 8.8 Hz),7.60-7.54 (m, 3H), 7.03 (d, 2H, J =8.8 Hz), 6.94 (d, 2H, J =3.1 Hz),5.57 (s, 2H), 3.59 (s, 6H), 3.57 (s, 3H). LCMS: ret. time: 13.00 min.;purity: 97%; MS (m/e): 547 (MH⁺). 7.3.1086N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935368) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamimeand 6-aminoindazoline were reacted to giveN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.73 (s, 1H), 9.67 (s, 1H), 9.46 (s, 1H), 8.21 (d,1H, J =3.5 Hz), 8.17 (app d, 1H, J =8.8 Hz), 8.04 (br s, 1H), 7.97 (dt,1H, J =2.4 and 9.3 Hz), 7.89 (s, 1H), 7.58 (d, 1H, J =8.8 Hz), 7.47 (d,1H, J =9.3 Hz), 7.27 (dd, 1H, J =1.7 and 8.8 Hz). LCMS: ret. time: 13.08min.; purity: 96%; MS (m/e): 439 (MH⁺). 7.3.1087N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine(R935369) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-trifluoromethoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provideN4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.62 (s, 1H), 9.29 (s, 1H), 8.17 (d, 1H, J =3.5 Hz),8.11 (t, 1H, J =2.4 Hz), 8.02 (app s, 1H), 7.88-7.82 (m, 3H), 7.53 (d,1H, J =9.3 Hz), 7.47 (d, 2H, J =8.8 Hz), 4.52 (t, 2H, J =7.0 Hz), 2.48(t, 2H, J =7.0 Hz), 2.48 (d, 3H, J =4.7 Hz). LCMS: ret. time: 10.51min.; purity: 99%; MS (m/e): 524 (MH⁺). 7.3.1088N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935370) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-trifluoromethoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with DIBAL-H to produceN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.62 (s, 1H), 9.28 (s, 1H), 8.17 (d, 1H, J =3.5 Hz),8.11 (s, 1H), 8.02 (s, 1H), 7.85 (s, 2H), 7.53 (t, 2H, J =8.8 Hz), 7.46(t, 1H, J =8.8 Hz), 4.56 (t, 1H, J =5.8 Hz), 4.38 (t, 2H, J =6.4 Hz),3.35 (dd, 2H, J =5.8 and 6.4 Hz), 1.93 (q, 2H, J =6.4 Hz). LCMS: ret.time: 11.33 min.; purity: 99%; MS (m/e): 497 (MH⁺). 7.3.1089 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935371) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-dichlorophenyl)-5-fluoro 4-pyrimidineamime and5-aminoindazoline were reacted to give N4-(3,4-dichlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.90 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H, J =4.2 Hz),8.06 (t, 1H, J =2.3 Hz), 7.92 (s, 2H), 7.73 (d, 1H, J =8.8 Hz),7.51-7.40 (m, 3H). LCMS: ret. time: 9.83 min.; purity: 98%; MS (m/e):390 (MH⁺). 7.3.1090 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935372) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-dichlorophenyl)-5-fluoro 4-pyrimidineamine and6-aminoindazoline were reacted to give N4-(3,4-dichlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.82 (s, 1H), 9.63 (s, 1H), 9.48 (s, 1H), 8.22 (d,1H, J =4.3 Hz), 8.15 (t, 1H, J =2.3 Hz), 8.02 (s, 1H), 7.92-7.90 (m,2H), 7.59 (d, 1H, J =8.8 Hz), 7.52 (d, 1H, J =8.8 Hz), 7.26 (dd, 1H, J=1.7 and 8.8 Hz). LCMS: ret. time: 11.73 min.; purity: 99%; MS (m/e):390 (MH⁺). 7.3.1091 N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935373) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and5-aminoindazoline were reacted to give N4-(3,4-difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.40 (s, 1H), 10.11 (s, 1H), 8.25 (d, 1H, J =4.5Hz), 7.95 (s, 1H), 7.89 (app s, 2H), 7.49 (d, 1H, J =8.8 Hz), 7.37 (appd, 3H, J =8.2 Hz). LCMS: ret. time: 8.56 min.; purity: 99%; MS (m/e):401 (MH⁺). 7.3.1092 N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine(R935374) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and6-aminoindazoline were reacted to give N4-(3,4-difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.53 (s, 1H), 9.52 (s, 1H), 8.21 (d, 1H, J =4.5 Hz),8.10 (s, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.59 (d, 1H, J =8.8 Hz), 7.48(dt, 1H, J =2.3 and 8.8 Hz), 7.34 (d, 1H, J =8.2 Hz), 7.21 (dd, 1H, J=2.3 and 8.8 Hz). LCMS: ret. time: 11.29 min.; purity: 90%; MS (m/e):401 (MH⁺). 7.3.1093N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine(R935375) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(6-chloro-3-pyridyl)-5-fluoro-4-pyrimidineamine and5-amino-1-methylindazoline were reacted to giveN4-(6-chloro-3-pyridyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.96 (s, 1H), 9.58 (s, 1H), 8.86 (s, 1H), 8.25 (dt,1H, J =3.9 and 8.8 Hz), 8.20 (d, 1H, J =4.1 Hz), 8.04 (s, 1H), 7.55 (d,1H, J =8.8 Hz), 7.44 (d, 2H, J =8.8 Hz), 4.00 (s, 3H). LCMS: ret. time:8.95 min.; purity: 100%; MS (m/e): 370 (MH⁺). 7.3.1094N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine(R935376) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(6-chloro-3-pyridyl)-5-fluoro-4-pyrimidineamine and5-aminoindazoline were reacted to giveN4-(6-chloro-3-pyridyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.78 (s, 1H), 9.41 (s, 1H), 8.88 (s, 1H), 8.24 (d,1H, J =8.2 Hz), 8.18 (d, 1H, J =3.5 Hz), 8.06 (s, 1H), 7.92 (s, 1H),7.42 (app s, 3H). LCMS: ret. time: 7.87 min.; purity: 90%; MS (m/e): 356(MH⁺). 7.3.1095N4-(6-Chloro-3-pyridyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935377) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(6-chloro-3-pyridyl)-5-fluoro-4-pyrimidineamine and5-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(6-chloro-3-pyridyl-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.37 (s, 1H), 10.04 (s, 1H), 8.78 (s, 1H), 8.28 (d,1H, J =4.8 Hz), 8.20 (dt, 1H, J =2.8 and 8.8 Hz), 7.96 (s, 1H), 7.92 (s,1H), 7.65 (d, 1H, J =8.8 Hz), 7.45 (d, 1H, J =8.8 Hz), 7.41 (d, 1H, J=8.8 Hz), 4.59 (t, 2H, J =6.0 Hz), 3.97 (qt, 2H, J =7.0 Hz), 2.90 (t,2H, J =6.4 Hz), 1.06 (t, 3H, J =7.0 Hz). LCMS: ret. time: 10.87 min.;purity: 94%; MS (m/e): 456 (MH⁺). 7.3.1096N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine(R935378) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(6-chloro-3-pyridyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provideN4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.67 (s, 1H), 9.31 (s, 1H), 8.88 (s, 1H), 8.27 (dt,1H, J =3.0 and 8.8 Hz), 8.17 (d, 1H, J =3.5 Hz), 8.08 (s, 1H), 7.88 (s,1H), 7.83 (q, 1H, J =5.3 Hz), 7.53 (d, 1H, J =8.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 4.53 (t, 2H, J =7.0 Hz), 2.63 (t, 2H, J =7.0 Hz), 2.49 (d, 3H,J =5.3 Hz). LCMS: ret. time: 7.62 min.; purity: 89%; MS (m/e): 441(MH⁺). 7.3.1097N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine(R935379) In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(6-chloro-3-pyridyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with DIBAL-H to produceN4-(6-chloro-3-pyridyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆):. LCMS: ret. time: 8.02 min.; purity: 98%; MS (m/e):414 (MH⁺). 7.3.1098N4-(2,6-Dimethoxy-3-pyridyl)-5-fluoro-N2-[1-methylindazoline-5-yl]-2,4-pyrimidinediamine(R935380) In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(2,6-dimethoxy-3-pyridyl)-6-5-fluoro-4-pyrimidineamine and1-methyl-5-aminoindazoline were reacted to giveN4-(2,6-dimethoxy-3-pyridyl)-5-fluoro-N2-[1-methylindazoline-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.08 (s, 1H), 8.68 (s, 1H), 8.01 (d, 1H, J =4.1 Hz),7.96 (s, 1H), 7.76 (dd, 1H, J =4.1 and 8.8 Hz), 7.65 (s, 1H), 7.37 (d,1H, J =8.8 Hz), 7.34 (d, 1H, J =8.2 Hz), 6.46 (d, 1H, J =8.2 Hz), 3.94(s, 3H), 3.91 (s, 3H), 3.83 (s, 3H). LCMS: ret. time: 9.57 min.; purity:92%; MS (m/e): 396 (MH⁺). 7.3.1099 Additional 2,4-PyrimidinediamineCompounds R008951, R008952, R008953, R008955, R008956, R008958, R070153and R070790 (structures provided below) were purchased from ContactServices. Additional compounds whose structures are provided below weresynthesized using methods similar to those described in the previousexamples. 7.3.1100 Synthesis of Intermediates, 2,4-Pyrimidinediaminesand 2,4,6-Pyrimidinetriamines According to Schemes VIII and IX A varietyof intermediates and 2,4-pyrimidinediamine compounds were synthesizedaccording to Schemes VIII and IX. Scheme VIII is exemplified by thereaction of 2,4,6-trichloropyrimidine with 3-hydroxyaniline to form amixture of three compounds, which were separated and purified bychromotography. Scheme IX is exemplified by the reaction of2,4,5,6-tetrachloridepyrimidine with 3,4-ethylenedioxyaniline to form amixture of three compounds, which were separated and purified bychromotography. 7.3.1101 Reaction of 2,4,6-trichloropyrimidine with3-hydroxyaniline 4,6-Dichloro-N2-(3-hydroxyphenyl)-2-pyrimidineamine(R926407) N2,N4-Bis(3-hydroxyphenyl)-6-chloro-2,4-pyrimidinediamine(R926408) and N2,N4,N6-Tris(3-hydroxyphenyl)-2,4,6-pyrimidinetriamine(R926409) A mixture of 2,4,6-trichloroaniline (0.183 g, 1 mmol) and3-hydroxyaniline (0.327 g, 3 mmol) in 5 mL MeOH was heated at 100° C. ina sealed vial for 24 h. The reaction mixture was diluted with H₂O,acidified with 2N HCl and extracted with EtOAc (3 × 50 mL). Upon removalof solvent the residue was purified by chromatography (as well aspreparative TLC) to afford three products, mainly the mono-SNAr,4,6-dichloro-N2-(3-hydroxyphenyl)-2-pyrimidineamine (R926407),: ¹H NMR(CDCl₃): δ7.16 (t, 1H, J=8.1 Hz), 6.78 (m, 2H), 6.64 (dd, 1H, J=1.2 and8.1 Hz), 6.58 (s, 1H); LCMS: ret. time: 25.08 min.; purity: 99%; MS(m/e): 256 (M⁺); bis-SNAr product,N2,N4-bis(3-hydroxyphenyl)-6-chloro-2,4-pyrimidinediamine (R926408), ¹HNMR (CD₃OD): δ7.21 (m, 1H), 7.14-7.03 (m, 5H), 6.50 (m, 1H), 6.44 (m,1H), 6.16 (s, 1H); LCMS: ret. time: 25.14 min.; purity: 99%; MS (m/e):329 (M⁺); and tris-SNAr product,N2,N4,N6-tris(3-hydroxyphenyl)-2,4,6-pyrimidinetriamine (R926409), ¹HNMR (CD₃OD): δ7.29 (m, 1H), 7.12-7.05 (m, 5H), 7.02 (m, 2H), 6.88 (dd,2H, J=1.2 and 8.1 Hz), 6.46 (dd, 1H, J=1.5 and 8.1 Hz), 6.41 (dt, 1H);LCMS: ret. time: 20.49 min.; purity: 94%; MS (m/e): 402 (MH⁺). 7.3.1102N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-6-chloro-2,4-pyrimidinediamine(R926411) In like manner to the reaction of 2,4,6-trichloropyrimidinewith 3-hydroxyaniline, the reaction of 2,4,6-trichloropyrimidine withmethyl 4-aminophenoxyacetate gaveN2,N4-bis(4-methoxycarbonylmethyleneoxyphenyl)-6-chloro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.65 (bs, 1H), 7.40 (bd, 4H), 6.82 (bd, 4H), 6.00 (s,1H), 6.62 (bs, 4H), 3.78 (bs, 6H); LCMS: ret. time: 29.87 min.; purity:98%; MS (m/e): 473 (MH⁺). 7.3.1103 Reaction of 2,4,6-trichloropyrimidinewith 3,4-ethylenedioxyaniline4,6-Dichloro-N2-(3,4-ethylenedioxyphenyl)-2-pyrimidineamine (R926515)N2,N4-Bis(3,4-ethylenedioxyphenyl)-6-chloro-2,4-pyrimidinediamine(R926245) N2,N4,N6-Tris(3,4-ethylenedioxyphenyl)-2,4,6-pyrimidinetriamine (R926516) Amixture of 2,4,6-trichloroaniline (1 mmol) and 3,4-ethylenedioxyaniline(3 mmol) in 5 mL MeOH was heated at 100° C. in a sealed vial for 24 h.The reaction mixture was diluted with H₂O, acidified with 2N HCl andextracted with EtOAc (3 × 50 mL). Upon removal of solvent the residuewas purified by chromatography (as well as preparative TLC) to affordthree products, mainly the Mono-SNAr product,4,6-dichloro-N2-(3,4-ethylenedioxyphenyl)-2-pyrimidineamine (R926515).¹H NMR (CD₃OD): δ7.05 (s, 1H), 6.83 (m, 2H), 6.45 (bs, 1H), 4.20 (bs,4H); LCMS: ret. time: 29.75 min.; purity: 96%; MS (m/e): 298 (M⁺);Bis-SNAr product,N2,N4-bis(3,4-ethylenedioxyphenyl)-6-chloro-2,4-pyrimidinediamine(R926245): ¹H NMR (CDCl₃): δ7.23 (d, 1H, J=3 Hz), 6.90-6.70 (m, 6H),6.02 (s, 1H), 4.26 (bs, 4H), 4.23 (m, 4H); LCMS: ret. time: 31.34 min.;purity: 95%; MS (m/e): 413 (MH⁺) and Tris-SNAr product, N2,N4,N6-tris(3,4-ethylenedioxyphenyl)-2,4,6-pyrimidinetriamine (R926516) ¹H NMR(CD₃OD): δ7.16 (d, 1H, J=3Hz), 7.05 (bd, 1H), 6.99-6.90 (m, 3H),6.80-6.70 (m, 4H), 6.03 (s, 1H), 4.22 (s, 4H), 4.20 (s, 8H); LCMS: ret.time: 27.72 min.; purity: 61%; MS (m/e): 528 (M⁺). 7.3.1104 Reaction of2,4,6-trichloropyrimidine with ethyl-4-aminophenoxyacetate4,6-Dichloro-N2-(4-ethoxycarbonylmethyl)-4,6-dichloro-2-pyrimidineamine(R926549) 2,6-Dichloro-N4-(ethoxycarbonylmethyl)-4-pyrimidineamine(R926550) A mixture of 2,4,6-trichloroaniline (1 mmol) and ethyl2-aminoacetate (3 mmol) in 5 mL MeOH was heated at 100° C. in a sealedvial for 24 h. The reaction mixture was diluted with H₂O, acidified with2N HCl and extracted with EtOAc (3 × 50 mL). Upon removal of solvent theresidue was purified by chromatography (as well as preparative TLC) toafford three products, mainly the mono-SNAr product,4,6-dichloro-N2-(4-ethoxycarbonylmethyl)-4,6-dichloro-2-pyrimidineamine(R926549). ¹H NMR (CDCl₃): δ6.67 (s, 1H), 5.85 (bs, 1H), 4.23 (q, 2H,J=7.2 Hz), 4.19 (s, 2H), 1.29 (t, 3H, J=7.2 Hz); LCMS: ret. time: 26.18min.; purity: 100%; MS (m/e): 250 (MH⁺); and Mono-SNAr product,2,6-dichloro-N4-(ethoxycarbonylmethyl)-4-pyrimidineamine (R926550): ¹HNMR (CDCl₃): d 6.37 (bs, 1H), 4.28 (q, 2H, J=6.9 Hz), 4.19 (bs, 2H),1.31 (t, 3H, J=7.2 Hz) 7.3.11056-Chloro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(methoxycarbonylmethyl)-2,4-pyrimidinediamine(R926555) In like manner to the preparation of 4-[N-(L)-phenylalanineethyl ester]-N2-(3-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidineamine,the reaction of ethyl 4-aminophenoxyacetate with methyl 2-aminoacetategave6-chloro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(methoxycarbonylmethyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.40 (d, 2H, J=8.7 Hz), 6.86 (d, 2H, J=9.3 Hz), 5.97(s, 1H), 4.64 (s, 2H), 4.26 (q, 2H, J=7.2 Hz), 4.14 (q, 2H, J=6.9 Hz),4.05 9s, 2H), 1.25 (m, 6H); LCMS: ret. time: 26.21 min.; purity: 93%; MS(m/e): 409 (MH⁺). 7.3.1106 Reaction of 3,4-ethylenedioxyaniline with2,4,5,6-tetrachloropyrimidine.N4-(3,4-Ethylenedioxyphenyl)-2,5,6-trichloro-4-pyrimidineamine (R926466)N2,N4-Bis(3,4-ethylenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926467) andN4,N6-Bis(3,4-ethylenedioxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine(R926468) A mixture of 3,4-ethylenedioxyaniline (0.775 g, 5 mmol) and2,4,5,6-tetrachloropyrimidine (0.434 g, 2 mmol) in the presence of DIPEA(1.043 mL, 6 mmol) in EtOAc (10 mL) was heated at 80° C. for 3 days. Thereaction was diluted with water (50 mL), acidified (2N HCl) andextracted with EtOAc (3 × 50 mL). The residue obtained after removal ofsolvent was chromatographed using 5-30% EtOAc/hexanes to obtain threeproducts viz.N4-(3,4-Ethylenedioxyphenyl)-2,5,6-trichloro-4-pyrimidineamine(R926466): ¹H NMR (CDCl₃): δ7.18 (d, 1H, J=2.7 Hz), 6.92 (dd, 1H, J=2.1and 8.7 Hz), 6.87 (d, 1H, J=9 Hz); LCMS: ret. time: 33.53 min.; purity:100%; MS(m/e): 292 (MH⁺);N2,N4-Bis(3,4-ethylenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926467): ¹H NMR (CDCl₃): δ7.11 (d, 1H, J=2.4 Hz), 7.06 (d, 1H, J=2.1Hz), 7.04 (s, 1H0, 6.94 (m, 2H), 6.84 (d, 1H, J=8.1 Hz), 6.76 (bd, 2H,J=8.7 Hz), 4.27 (bs, 4H), 4.24 (bs, 1H); LCMS: ret. time: 26.54 min.;purity: 87%; MS(m/e): 364 (MH⁺); andN4,N6-Bis(3,4-ethylenedioxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine(R926468): ¹H NMR (CDCl₃): δ7.07 (t, 1H, J=2.4 Hz), 6.99 (s, 2H), 6.83(dd, 2H, J=2.4 and 8.7 Hz), 6.75 (dd, 2H, J=1.8 and 9 Hz), 4.19 (bs,4H); LCMS: ret. time: 34.70 min.; purity: 99%; MS(m/e): 365 (MH⁺).7.3.1107 Reaction of 2,4,5,6-tetrachloropyrimidine withethyl-4-aminophenoxyacetateN4-(4-Ethoxycarbonylmethyleneoxyphenyl)-2,5,6-trichloro-4-pyrimidineamine(R926568)N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926569)N2,N5-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-2,5-pyrimidinediamine(R926570) In like manner to the reaction of 2,4,6-trichloropyrimidinewith 3,4-ethylenedioxyaniline, the reaction of2,4,5,6-tetrachloropyrimidine with ethyl 4-aminophenoxyacetate gave amixture of mono-SNAr product, N4-(4-ethoxycarbonylmethyleneoxyphenyl)-2,5,6-trichloro-4-pyrimidineamine (R926568): ¹H NMR(CDCl₃): δ7.46 (dd, 2H, J=2.4 and 6.9 Hz), 7.3 (s, 1H), 6.95 (dd, 2H,J=2.4 and 6.9 Hz), 4.63 (s, 2H), 4.28 (q, 2H, J=7.2 Hz), 1.30 (t, 3H,J=7.2 Hz); LCMS: ret. time: 30.62 min.; purity: 99%; MS (m/e): 378(MH⁺); Bis-SNAr product, N2,N4-bis((4-ethoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine (R926569): ¹H NMR (CDCl₃):δ7.42 (d, 2H, J=9 Hz), 7.35 (d, 2H, J=8.7 Hz), 6.90 (d, 2H, J=9Hz), 6.83(d, 2H, J=8.7 Hz), 4.67 (s, 2H), 4.60 (s, 2H), 4.28 (2q, 4H, J=4.8 Hz),1.31 (2t, 6H, J=6.3 Hz); LCMS: ret. time: 33.09 min.; purity: 85%; MS(m/e): 537 (MH⁺) and Bis-SNAr product,N2,N5-bis((4-ethoxycarbonylmethyleneoxyphenyl)-2,5-pyrimidinediamine(R926570): ¹H NMR (CDCl₃): δ7.45 (d, 4H, J=8.7 Hz), 6.92 (d, 4H, J=9Hz),6.85 (s, 1H), 4.61 (s, 4H), 4.26 (q, 4H, J=6.9 Hz), 1.30 (t, 6H, J=7.2Hz); LCMS: ret. time: 31.66 min.; purity: 97%; MS (m/e): 535 (MH⁺).7.3.1108 Reaction of 2,4,5,6-tetrachloropyrimidine withtert-Butyl-4-aminophenoxyacetate,N4-(4-tert-Butoxyoxycarbonylmethyleneoxyphenyl)-2,5,6-trichloro-4-pyrimidineamine(R926575),N2,N4-Bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926576) andN4,N6-Bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine(R926577) In like manner to the reaction of 2,4,6-trichloropyrimidinewith 3,4-ethylenedioxyaniline, the reaction of2,4,5,6-tetrachloropyrimidine with tert-butyl-4-aminophenoxyacetate gavea mixture of mono-SNAr product, N4-(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-2,5,6-trichloro-4-pyrimidineamine (R926575): ¹H NMR(CDCl₃): δ7.45 (dd, 2H, J=2.4 and 7.2 Hz), 6.93 (dd, 2H, J=2.4 and 7.2Hz), 4.52 (s, 2H); LCMS: ret. time: 32.56 min.; purity: 100%; MS (m/e):402 (MH⁺); Bis-SNAr product,N2,N4-bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine(R926576):¹H NMR (CDCl₃): δ7.42 (d, 2H, J=9 Hz), 7.35 (d, 2H, 9.3 Hz),7.08 (s, 1H), 6.90 (d, 2H, J=9.3 Hz), 6.82 (d, 2H, J=8.7 Hz), 4.53 (s,2H), 4.49 (s, 2H), 1.50 (s, 9H), 1.49 (s, 9H); LCMS: ret. time: 36.04min.; purity: 92%; MS (m/e): 591 (MH⁺) and Bis-SNAr product,N4,N6-bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine(R926577): ¹H NMR (CDCl₃): δ7.43 (d, 4H, J=8.7 Hz), 6.90 (dd, 4H, J=9.3Hz), 4.50 (s, 2H), 1.49 (s, 18H); LCMS: ret. time: 35.31 min.; purity:100%; MS (m/e): 591 (MH⁺). 7.3.1109 Reaction of2,4,5,6-tetrachloropyrimidine with 3-hydroxyaniline,N4-(3-Hydroxyphenyl)-2,5,6-trichloro-4-pyrimidineamine (R926590),N2,N4-Bis(3-hydroxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine (R926591)and N4,N6-Bis(3-hydroxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine(R926592) In like manner to the reaction of 2,4,6-trichloropyrimidinewith 3,4-ethylenedioxyaniline, the reaction of2,4,5,6-tetrachloropyrimidine with tert-butyl-4-aminophenoxyacetate gavea mixture of mono-SNAr product,N4-(3-hydroxyphenyl)-2,5,6-trichloro-4-pyrimidineamine (R926590): ¹H NMR(CDCl₃): δ7.38 (bs, 1H), 7.32 (t, 1H, J=2.4 Hz), 7.22 (s, 1H), 7.01 (dd,1H, J=1.2 and 8.1 Hz), 6.68 (dd, 1H, J=1.8 and 8.1 Hz); LCMS: ret. time:26.09 min.; purity: 99%; MS (m/e): 292 (MH⁺); Bis-SNAr product,N2,N4-bis(3-hydroxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine (R926591):¹H NMR (CDCl₃): δ7.45 (s, 1H), 7.30 (t, 1H, J=2.4 Hz), 7.18 (t, 1H,J=2.4 Hz), 7.07 (t, 1H, j=6.6 Hz), 6.98 (t, 1H, J=8.1 Hz), 6.75 (m, 2H),6.54 (dd, 1H, J=2.4 and 8.1 Hz); LCMS: ret. time: 26.54 min.; purity:87%; MS (m/e): 364 (MH⁺); and Bis-SNAr product,N4,N6-bis(3-hydroxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine (R926592):¹H NMR (CDCl₃): δ7.34 (t, 2H, j=2.4 Hz), 7.21 (t, 2H, J=7.5 Hz), 6.98(m, 4H), 6.60 (m, 2H); LCMS: ret. time: 25.38 min.; purity: 73%; MS(m/e): 364 (MH⁺). 7.3.1110N2,N4-Bis(3-hydroxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine(R926595) The reaction of N2N4-bis(3-hydroxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine (18 mg, 0.05mmol) with sodium thiomethoxide (10 mg, 0.15 mmol) in absolute EtOH (1mL) was heated at 80° C. for 3 days, diluted with H₂O, extracted withEtOAc (3 × 10 mL), and solvent was evaporated to obtain the N2N4-bis(3-hydroxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine(R926595). ¹H NMR (CD₃OD): δ7.40-7.2 (m, 2H), 7.20-6.80 (m, 3H), 6.67(m, 1H), 6.45-6.30 (m, 2H), 2.4 (s, 3H); LCMS: ret. time: 27.78 min.;purity: 80%; MS (m/e): 376 (MH⁺). 7.3.1111N2,N4-Bis(3,4-ethyelenedioxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine(R926475) In like manner to the preparation of N2N4-bis(3-hydroxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine(R926595), the reaction ofN2,N4-bis(3,4-ethyelenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediaminegaveN2,N4-bis(3,4-ethyelenedioxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.10 (bd, 2H), 7.00-6.00 (m, 4H), 4.23 (s, 4H), 4.10(s, 4H), 2.60 (s, 3H); LCMS: ret. time: 36.14 min; purity: 100%; MS(m/e): 459 (MH⁺). 7.3.1112 6-ChloroN4-(3-hydroxyphenyl)-4-pyrimidineamine (R926530) The reaction of4,6-dichloropyrimidine with excess 3-hydroxyaniline in MeOH at 80 0° C.for 24 h followed by dilution with water and acidification gave thecrude product which was purified by silica gel column chromatography toobtain 6-chloro N4-(3-hydroxyphenyl)-4-pyrimidineamine. ¹H NMR (CD₃OD):δ8.36 (d, 1H, J=1.2 Hz), 7.15 (t, 1H, J=8.4 Hz), 6.93 (dd, 1.2 and 8.1Hz), 6.74 (d, 1H, J=1.2 Hz), 6.55 (dd, 1.8 and 8.1 Hz); LCMS (m/e): ret.time: 19.75 min.; purity: 99%; MS (m/e): 222 (MH⁺). 7.3.1113N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine(R925784) A mixture ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine (20 mg,0.044 mmol) and phenylboronic acid (6.9 mg, 0.057 mmol) in DME (1 mL)was prepared in a sealed tube and purged with N₂.Tetrakis(triphenylphosphine) palladium(0) (0.002 mmol) was added, andthe reaction tube sealed and heated at 80° C. overnight. After cooling,the reaction mixture was diluted with EtOAc, washed with 1N NaOH andbrine, dried (MgSO₄), and concentrated. The residue was purified bypreparative TLC (40% EtOAc/hexanes) to affordN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ7.77 (s, 1H), 7.52-7.36 (m, 5H), 7.10 (d, 1H, J=2.4 Hz),7.05 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=2.4 and 8.7 Hz), 6.87 (dd, 1H,J=2.4 and 8.7 Hz), 6.73 (d, 1H, J=8.7 Hz), 6.69 (d, 1H, J=8.7 Hz),4.23-4.20 (m, 8H); LCMS: ret. time: 25.38 min.; purity: 100 %; MS (m/e):455 (MH⁺). 7.3.1114N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(2-furanyl)-2,4-pyrimidinediamine(R925785) In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine andfuran-2-boronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(2-furanyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.13 (s, 1H), 7.61 (d, 1H, J=1.8 Hz), 7.12 (d, 1H,J=2.4 Hz), 7.08 (d, 1H, J=2.4 Hz), 6.93 (td, 2H, J=2.4 and 8.7 Hz), 6.78(d, 1H, J=8.7 Hz), 6.68 (d, 1H, J=8.7 Hz), 6.58 (d, 1H, J=2.4 Hz), 6.54(dd, 1H, J=1.8 and 3.6), 4.24 (s, 4H), 4.20 (bs, 4H); LCMS: ret. time:15.03 min.; purity: 88 %; MS (m/e): 445 (MH⁺). 7.3.1115N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-chlorophenyl)-2,4-pyrimidinediamine(R925786) In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and4-chlorophenylboronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-chlorophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.99 (bs, 1H), 8.05 (bs, 1H), 7.85 (s, 1H), 7.50-7.42(m, 4H), 7.23 (bs, 1H), 7.10 (dd, 1H, J=2.4 and 8.7 Hz), 7.06 (t, 1H,J=2.4 Hz), 7.00-6.94 (m, 1H), 6.73 (d, 1H, J=8.7 Hz), 6.63 (d, 1H, J=8.7Hz); LCMS: ret. time: 16.12 min.; purity: 86 %; MS (m/e): 490 (MH⁺).7.3.1116N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(3-chlorophenyl)-2,4-pyrimidinediamine(R925787) In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and3-chlorophenylboronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(3-chlorophenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.77 (s, 1H), 7.45-7.41 (m, 2H), 7.38-7.33 (m, 2H),7.09 (d, 1H, J=2.4 Hz), 7.01 (d, 1H, J=2.4 Hz), 6.92 (dd, 1H, J=2.4 and9.0 Hz), 6.86 (dd, 1H, J=2.4 and 8.7 Hz), 6.74 (d, 1H, J=8.7 Hz), 6.67(d, 1H, J=8.7 Hz), 4.21 (s, 4H), 4.19 (s, 4H); LCMS: ret. time: 27.18min.; purity: 95 %; MS (m/e): 490 (MH⁺). 7.3.1117N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine(R925813) In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and(4-methoxycarbonylphenyl)boronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 26.35 min.; purity: 90 %; MS (m/e): 514 (MH⁺). 7.3.1118N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-hydroxyphenyl)-2,4-pyrimidinediamine(R925816) In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and4-hydroxyphenylboronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.53 (s, 1H), 8.92 (s, 1H), 7.78 (s, 1H), 7.74 (bs,1H), 7.24 (bs, 1H), 7.22 (d, 2H, J=8.7 Hz), 7.12-7.09 (m, 2H), 6.97 (dt,1H, J=2.4 and 8.7 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.72 (d, 1H, J=8.1 Hz),6.62 (d, 1H, J=9.0 Hz), 4.19 (s, 4H), 4.17 (s, 4H); LCMS: ret. time:23.51 min.; purity: 95 %; MS (m/e): 471 (MH⁺). 7.3.1119N2,N4-Bis(3-hydroxyphenyl)-5-phenyl-2,4-pyrimidinediamine (R925783) In amanner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine andphenylboronic acid were reacted to yieldN2,N4-bis(3-hydroxyphenyl)-5-phenyl-2,4-pyrimidinediamine. ¹H NMR(CD₃OD): δ7.85 (bs, 1H), 7.54-7.38 (m, 5H), 7.13-7.11 (m, 2H). 7.10-7.04(m, 3H), 6.97 (dt, 1H, J=1.8 and 8.1 Hz), 6.54 (ddd, 1H, J=1.9, 2.4, and7.2 Hz), 6.44 (dt, 1H, J=1.8 and 6.0 Hz); LCMS: ret. time: 20.66 min.;purity: 96 %; MS (m/e): 371 (MH⁺). 7.3.1120N2,N4-Bis(3-hydroxyphenyl)-5-(3,4-methylenedioxyphenyl)-2,4-pyrimidinediamine(R925788) In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine and3,4-methylenedioxyphenylboronic acid were reacted to yieldN2,N4-bis(3-hydroxyphenyl)-5-(3,4-methylenedioxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.82 (s, 1H), 7.13-7.06 (m, 3H), 7.04-7.01 (m, 2H),6.97 (dt, 1H, J=1.2 and 8.7 Hz), 6.94-6.88 (m, 3H), 6.52 (ddd, 1H,J=1.2, 2.4, and 6.9 Hz), 6.42 (dt, 1H, J=2.1 and 7.5 Hz), 6.01 (s, 2H);LCMS: ret. time: 21.11 min.; purity: 99 %; MS (m/e): 415 (MH⁺). 7.3.1121N2,N4-Bis(3,4-ethylenedioxyphenyl)-6-phenyl-2,4-pyrimidinediamine(R925811) In a manner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3,4-ethylenedioxyphenyl)-6-chloro-2,4-pyrimidinediamine andphenylboronic acid were reacted to yieldN2,N4-bis(3,4-ethylenedioxyphenyl)-6-phenyl-2,4-pyrimidinediamine. ¹HNMR (CD₃OD): δ7.97-7.92 (m, 2H), 7.46-7.43 (m, 3H), 7.35 (d, 1H, J=2.7Hz), 7.19 (d, 1H, J=2.4 Hz), 7.07-7.00 (m, 2H), 6.75 (t, 2H, J=8.7 Hz),6.50 (s, 1H), 4.24-4.19 (m, 8H); LCMS: ret. time: 26.68 min.; purity: 97%; MS (m/e): 455 (MH⁺). 7.3.1122N2,N4-Bis(3-hydroxyphenyl)-6-phenyl-2,4-pyrimidinediamine (R925812) In amanner similar to the preparation ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine,N2,N4-bis(3-hydroxyphenyl)-6-chloro-2,4-pyrimidinediamine andphenylboronic acid were reacted to yieldN2,N4-bis(3-hydroxyphenyl)-6-phenyl-2,4-pyrimidinediamine. LCMS: ret.time: 22.13 min.; purity: 90 %; MS (m/e): 371 (MH⁺). 7.3.1123N2-(3-Aminocarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926747) The hydrolysis ofN2-(3-cyanomethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediaminegaveN2-(3-aminocarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: ret. time: 16.76 min.; purity: 93 %; MS (m/e): 412 (MH⁺). 7.3.1124N2,N4-Bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine (R926461) Thereaction of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediaminewith 2 equivalents of sodium methoxide in methanol gave the requisitecompound, N2,N4-bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (D₂O): δ7.65 (bd, 1H), 7.00-6.90 (m, 2H), 6.71 (m, 2H), 6.55 (dd,1H, J=1.2 and 6.3 Hz), 6.31 (bd, 1H, J=8.1 Hz), 6.23 (bd, 1H, J=8.7 Hz);¹⁹F NMR (D₂O): - 47016; LCMS: ret. time: 15.68 min.; purity: 99%; MS(m/e): 313 (MH⁺). 7.3.11255-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,4,5,6-tetrahydro-2-pyrimidyl)methyleneoxyphenyl]-2,4-pyrimidinediamine(R945169) The reaction ofN2-(4-cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand HCl in ethanol, followed by 1,3-diaminopropane in methanol at 100°C. gave5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,4,5,6-tetrahydro-2-pyrimidyl)methyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ2.05 (p, J=5.7 Hz, 2H), 3.49 (t, J=5.7 Hz, 4H), 4.84(s, 2H), 6.56 (ddd, J=2.1, 3.6 and 5.4 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H),7.11-7.13 (m, 2H), 7.21 (m, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.87 (d, J=3.9Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): δ- 168.66; LCMS: ret. time: 12.77min.; purity: 97.61%; MS (m/e): 409.08 (MH⁺). 7.3.11265-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-[(4,4-dimethyl-3-oxazolin-2-yl)methyleneoxy]phenyl]-2,4-pyrimidinediamine(R926702)N2-[4-(cyanomethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineand 2-amino-2-methylpropanol were reacted to yield5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-[(4,4-dimethyl-3-oxazolin-2-yl)methyleneoxy]phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.87 (d, 1H, J=3.6 Hz), 7.37 (t, 1H, J=2.4 Hz), 7.34(d, 2H, J=9.0 Hz), 7.14 (t, 1H, J=8.1 Hz), 6.94 (bs, 1H), 6.90 (d, 2H,J=9.0 Hz), 6.78 (dd, 1H, J=2.4 and 8.4 Hz), 6.74 (d, 1H, J=3.0 Hz), 6.62(ddd, 1H, J=1.2, 2.4, and 8.4 Hz), 4.67 (s, 2H), 4.02 (s, 2H), 1.25 (s,6H); ¹⁹F NMR (CDCl₃): -47399; LCMS: ret. time: 13.82 min.; purity: 98%;MS (m/e): 425 (M+2H). 7.3.1127N4-(3-Carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950290) A mixture of equimolar amounts of2-chloro-N4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-4-aminopyridine and3-ethoxycarbonylmethyleneoxyaniline in MeOH in a pressure tube at 110°C. for 24 h or in EtOH using microwave at 175° C. for 10-20 min followedby aqueous work up gaveN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 97.8%; MS (m/e): 443.20 (MH⁺). 7.3.1128N4-(3-Carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine(R950291) The reaction ofN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(0.1 g) and LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h atroom temperature followed by treatment with aqueous HCl gave the solid.The resulting solid was filtered, washed with water and dried to giveN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 91.5%; MS (m/e): 415.16 (MH⁺). 7.3.1129N4-(3-Methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950293) A solution ofN4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a 4 M solution of HCl in dioxane. Themixture was stirred for 1 hour at 22° C., concentrated to dryness andpurified by flash chromatography on silica gel to giveN4-(3-methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ10.30 (s, 1H), 10.13 (s, 1H), 8.22 (d,1H, J=5.3 Hz), 7.96 (d, 1H, J=2.4 Hz), 7.71 (dd, J =2.4, 9.0 Hz, 1H),6.95-7.11 (m, 4H), 6.51 (m, 1H), 4.56 (s, 2H), 4.09 (q, J =7.2 Hz, 2H),3.72 (s, 3H), 1.14 (j, J =7.2 Hz, 3H); LCMS: purity: 96.8%; MS (m/e):457.25 (MH⁺). 7.3.1130N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950294) A mixture of equimolar amounts of2-chloro-N4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-4-aminopyridineand 3-ethoxycarbonylmethyleneoxyaniline in EtOH using microwave at 175°C. for 10-20 min followed by aqueous work up gaveN4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 92.1%; MS (m/e): 469.26 (MH⁺). 7.3.1131N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950295) A mixture of equimolar amounts of2-chloro-N4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-4-aminopyridineand 3-ethoxycarbonylmethyleneoxyaniline in MeOH in a pressure tube at110° C. for 24 h followed by aqueous work up gaveN4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 87.6%; MS (m/e): 455.26 (MH⁺). 7.3.1132N4-(4-Ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950296) A solutionofN4-(4-ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein EtOH was treated with the HCl salt of methylamine. The mixture wasstirred for 4 hours at 100° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 87.4%; MS (m/e): 468.29 (MH⁺). 7.3.1133N4-(4-Carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950344) A mixture ofequimolar amounts of2-chloro-N4-(4-carboxyethyleneoxyphenyl)-5-fluoro-4-aminopyridine and3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressure tubeat 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20 minfollowed by aqueous work up gaveN4-(4-carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 97.8%; MS (m/e): 456.32 (MH⁺). 7.3.1134N4-(2,3-Dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950345) A solution ofN4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein TfOH was heated for 2 hours at 100° C. Aqueous work up followed byflash chromatography on silica gel gaveN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 92.2%; MS (m/e): 435.95 (MH⁺). 7.3.1135N4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950346) A solution ofN4-(4-carboxyethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a 4 M solution of HCl in dioxane. Themixture was stirred for 1 hour at 22° C., concentrated to dryness andpurified by flash chromatography on silica gel to giveN4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 85.2%; MS (m/e): 468.01 (MH⁺). 7.3.1136N4-(4-Hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950347) The reaction ofN4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h at roomtemperature followed by treatment with aqueous HCl gave a pale yellowsolid. The resulting solid was filtered, washed with water and dried togiveN4-(4-hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 94.7%; MS (m/e): 382.03 (MH⁺). 7.3.1137N4-(2,3-Dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950348) A mixtureN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.5%; MS (m/e): 451.00 (MH⁺). 7.3.1138N4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950349) A solution ofN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeOH was treated with a sodiumcyanoborohydride. The mixture wasstirred for 1 hour at 22° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.19 (s, 1H), 9.09 (s, 1H), 8.03 (d,1H, J=2.4 Hz), 7.28-7.93 (m, 5H), 7.07 (t, 1H, J =7.2 Hz), 6.71 (d, 1H,J =7.2 Hz), 6.44 (dd, 1H, J =2.6, 7.2 Hz), 5.31 (d, 1H, J =5.1 Hz),4.14-4.59 (m, 3H), 4.30 (s, 2H), 2.63 (d, 3H, J =4.8 Hz), 1.82-2.03 (m,2H); LCMS: purity: 93.3%; MS (m/e): 440.15 (MH⁺). 7.3.1139N4-(2,3-Dihydro-4-O-methyloxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950356) A mixtureN4-(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand methoxyamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 85.5%; MS (m/e): 465.10 (MH⁺). 7.3.1140N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950368) A mixtureN4-(4-azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand Pd/C (10%) in MeOH was hydrogenated at 22° C. for 6 hours (40 psi).The mixture was filtered and concentrated to dryness to giveN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.60 (s, 1H), 9.46 (s, 1H), 8.73 (bs,3H), 8.00-8.10 (m, 3H), 7.47 (s, 1H), 7.42 (m, 1H), 7.29 (d, 1H, J =7.2Hz), 7.11 (t, 1H, J =7.2 Hz), 6.82 (d, 1H, J 7.0 Hz), 6.46 (m, 1H),4.23-4.46 (m, 3H), 4.31 (s, 3H), 2.63 (d, 3H, J =4.8 Hz), 2.09-2.29 (m,2H); LCMS: purity: 97.6%; MS (m/e): 438.98 (MH⁺). 7.3.1141N4-(3-Methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950371) A mixture of equimolaramounts of 2-chloro-N4-(3-methylcarbonylphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ10.16 (s, 1H), 9.82 (s, 1H), 8.24 (d,1H, J=2.4 Hz), 8.15 (s, 1H), 7.91-8.07 (m, 2H), 7.70 (d, 1H, J=7.0 Hz),7.49 (t, 1H, J =7.2 Hz), 7.08-7.21 (m, 3H), 6.56 (d, 1H, J =7.2 Hz),4.30 (s, 3H), 2.62 (d, 3H, J =4.8 Hz), 2.48 (s, 3H); LCMS: purity:93.8%; MS (m/e): 410.50 (MH⁺). 7.3.1142N4-(3-Phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950372) A mixture of equimolaramounts of 2-chloro-N4-(3-phenylcarbonylphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 86.0%; MS (m/e): 472.50 (MH⁺). 7.3.1143N4-(3-Methylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950373) A mixtureN4-(3-methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(3-methylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ11.21 (s, 1H), 10.11 (s, 1H), 9.85 (s,1H), 6.54-8.23 (m, 9H), 4.32 (s, 2H), 2.63 (d, J =7.0 Hz, 3H), 2.47 (s,3H); LCMS: purity: 92.4%; MS (m/e): 425.28 (MH⁺). 7.3.1144N4-(3-Phenylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950374) A mixtureN4-(3-phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN4-(3-phenylcarbonyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ11.63 (s, 1H), 10.30 (s, 1H), 9.85 (s,1H), 6.44-8.43 (m, 14H), 4.42 (s, 2H), 2.63 (d, J =7.0 Hz, 3H); LCMS:purity: 92.4%; MS (m/e): 487.31 (MH⁺). 7.3.1145N2,N4-Bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950376) A mixture of 2,4-dichloro-5-fluoropyridine and threeequivalents of 3-acetophenone in MeOH in a pressure tube at 110° C. for24 h or in EtOH using microwave at 175° C. for 10-20 min followed byaqueous work up gaveN2,N4-bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine as awhite solid. LCMS: purity: 93.1%; MS (m/e): 365.19 (MH⁺). 7.3.1146N2,N4-Bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine(R950377) A mixture of 2,4-dichloro-5-fluoropyridine and threeequivalents of 3-benzophenone in MeOH in a pressure tube at 110° C. for24 h or in EtOH using microwave at 175° C. for 10-20 min followed byaqueous work up gaveN2,N4-bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine as awhite solid. LCMS: purity: 95.7%; MS (m/e): 489.29 (MH⁺). 7.3.1147N2,N4-Bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950378) A solution ofN2,N4-bis(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediaminein TfOH was heated for 2 hours at 100° C. Aqueous work up followed byflash chromatography on silica gel gaveN2,N4-bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.36 (s, 1H), 9.14 (s, 1H), 8.06 (d,1H, J=2.4 Hz), 7.72-7.99 (m, 3H), 6.97 (d, J =7.2 Hz, 1H), 6.87 (d, J=7.2 Hz, 1H), 4.42-4.52 (m, 4H), 2.70-2.78 (m, 4H); LCMS: purity: 94.3%;MS (m/e): 484.50 (MH⁺). 7.3.1148N2,N4-Bis(3-methylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine(R950379) A mixture ofN2,N4-bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine andhydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(3-methylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. ¹H NMR (DMSO): δ11.21 (s, 1H), 10.11 (s, 1H), 9.85 (s,1H), 6.54-8.23 (m, 9H), 4.32 (s, 2H), 2.63 (d, J =7.0 Hz, 3H), 2.47 (s,3H); LCMS: purity: 92.1%; MS (m/e): 393.06 (M-H⁻). 7.3.1149N2,N4-Bis(3-phenylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine(R950380) A mixture ofN2,N4-bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine andhydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(3-phenylcarbonyloximephenyl)-5-fluoro-2,4-pyrimidinediamine asa white solid. LCMS: purity: 93.3%; MS (m/e): 486.05 (M-H⁻). 7.3.1150N2,N4-Bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950381) A mixture ofN2,N4-bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamineand hydroxylamine (20 equivalents) in pyridine at 22° C. for 16 hoursfollowed by aqueous work up gaveN2,N4-bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamineas a white solid. LCMS: purity: 98.1%; MS (m/e): 449.03 (M-H⁻). 7.3.1151N4-(4-Acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950382) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein pyridine was treated with acetic anhydride at 22° C. for 16 hours.Aqueous work up gaveN4-(4-acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ10.43 (bs, 1H), 9.62 (bs, 1H), 8.03(d, 1H, J =2.4 Hz), 7.10-7.83 (m, 7H), 6.83 (d, 1H, J =7.4 Hz), 6.52 (d,1H, J =7.2 Hz), 5.01 (m, 1H), 4.75 (s, 2H), 4.03-4.32 (m, 2H), 2.62 (s,3H), 2.23 (s, 3H), 1.93-2.13 (m, 2H); LCMS: purity: 92.1%; MS (m/e):393.06 (M-H⁻). 7.3.1152N4-(4-Azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950383) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry THF was treated with 2 equivalents of DPPA and DBU. The mixturewas stirred for 3 hours at 22° C., concentrated to dryness and purifiedby flash chromatography on silica gel to giveN4-(4-azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ10.09 (bs, 1H), 9.83 (bs, 1H), 8.18(d, 1H, J =2.4 Hz), 7.97 (m, 1H), 7.11-7.61 (m, 6H), 6.82 (d, 1H, J =7.8Hz), 6.62 (d, 1H, J =7.2 Hz), 4.78 (s, 2H), 4.03-4.33 (m, 3H), 2.62 (s,3H), 1.93-2.13 (m, 2H); LCMS: purity: 97.9%; MS (m/e): 463.07 (MH⁺).7.3.1153N4-(4-Benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950385) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein THF was treated with bortrifluoride etherate at 80° C. for 8 hours.Aqueous work up gaveN4-(4-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.18 (s, 1H), 9.14 (s, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.93 (bs, 1H), 5.86-7.48 (m, 9H) 4.73-4.74 (m, 2H), 4.33(s, 2H), 2.62 (s, 3H); LCMS: purity: 96.5%; MS (m/e): 420.07 (M-H⁻).7.3.1154N4-(3-Hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950386) A mixture of equimolar amounts of2-chloro-N4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethylene oxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.2%; MS (m/e): 410.5 (MH⁺). 7.3.1155N4-(3-Amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950388) A mixture of2-chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-aminopyridine and 3equivalents of 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in apressure tube at 110° C. for 24 h or in EtOH using microwave at 175° C.for 10-20 min followed by aqueous work up gaveN4-(3-amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 95.1%; MS (m/e): 427.18 (MH⁺). 7.3.1156N4-(4-Ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950389) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein HOAc was treated with sodium nitrate followed by addition ofconcentrated aqueous HCl and copper dichloride. The mixture was stirredfor 2 hours at 22° C. for 8 hours and purified by aqueous work upfollowed by column chromatography on silica gel to giveN4-(4-ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 82.3%; MS (m/e): 474.09 (M-H⁻). 7.3.1157N2,N4-Bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950391) A mixture of 2,4-dichloro-5-fluoropyridine and threeequivalents of 3-methoxycarbonyl-4-trifluoromethoxyaniline in MeOH in apressure tube at 110° C. for 24 h or in EtOH using microwave at 175° C.for 10-20 min followed by aqueous work upN2,N4-bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ9.96 (s, 1H), 9.82 (s, 1H), 8.16-8.26(m, 4H), 7.91 (dd, 1H, J =3.0, 7.2 Hz), 7.42 (d, 1H, J=7.2 Hz), 7.31 (d,1H, J=7.2 Hz), 3.77 (s, 3H), 3.75 (s, 3H); LCMS: purity: 93.0%; MS(m/e): 565.37 (MH⁺). 7.3.1158 N4-(3-Methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950392) A mixture of equimolar amounts of2-chloro-N4-(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-4-aminopyridineand 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH in a pressuretube at 110° C. for 24 h or in EtOH using microwave at 175° C. for 10-20min followed by aqueous work up gaveN4-(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 95.8%; MS (m/e): 510.41 (MH⁺). 7.3.1159N4-(4-Acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine (R950393) A solution ofN4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein dry MeCN was treated with concentrated sulfuric acid. The mixture wasstirred for 3 hours at 22° C., concentrated to dryness and purified byflash chromatography on silica gel to giveN4-(4-acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO): δ10.46 (bs, 1H), 9.52 (bs, 1H), 7.98(d, 1H, J =2.4 Hz), 7.12-7.73 (m, 7H), 6.66 (d, 1H, J =7.2 Hz), 6.49 (d,1H, J =7.2 Hz), 4.75 (s, 2H), 4.03-4.32 (m, 2H), 3.80 (m, 1H), 2.64 (s,3H), 2.143 (s, 3H), 1.90-2.11 (m, 2H); LCMS: purity: 92.1%; MS (m/e):393.06 (M-H⁻). LCMS: purity: 96.2%; MS (m/e): 479.13 (M-H⁻). 7.3.1160N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine HCl salt (R950399) A solution ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of 1 N aqueous HCl. The clearsolution was concentrated to dryness and the remaining solid was washedwith dry acetone to give the HCl salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 98.2%; MS (m/e): 438.98 (MH⁺). 7.3.1161N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine succinic acid salt (R950400) A solutionofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of succinic acid. The clearsolution was concentrated to dryness and the remaining solid wascrystallized from dry acetone to give the succinic acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 98.1%; MS (m/e): 438.98 (MH⁺). 7.3.1162N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine maleic acid salt (R950401) A solutionofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of maleic acid. The clear solutionwas concentrated to dryness and the remaining solid was crystallizedfrom dry acetone to give the maleic acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 97.9%; MS (m/e): 438.98 (MH⁺). 7.3.1163N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine fumaric acid salt (R950402) A solutionofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of fumaric acid. The clearsolution was concentrated to dryness and the remaining solid wascrystallized from dry acetone to give the fumaric acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 97.9%; MS (m/e): 438.98 (MH⁺). 7.3.1164N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine citric acid salt (R950403) A solutionofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of citric acid. The clear solutionwas concentrated to dryness and the remaining solid was crystallizedfrom dry acetone to give the citric acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 97.9%; MS (m/e): 438.98 (MH⁺). 7.3.1165N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine HNO₃ salt (R950404) A solution ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein MeOH was treated with 1 equivalent of 1 N aqueous HNO₃. The clearsolution was concentrated to dryness and the remaining solid was washedwith dry acetone to give the nitric acid salt ofN4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine as a white solid. LCMS:purity: 98.2%; MS (m/e): 438.98 (MH⁺). 7.4 Synthesis of ProdrugsExemplary prodrugs according to structural formula (II) were synthesizedas described below. 7.4.1N-2(4)-Acetyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926233) A mixture ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,acetyl chloride (4 equivalents), pyridine (4 equivalents) in CH₂Cl₂ wasstirred at room temperature for 48 h. After an aqueous work up theresidue was chromatographed on silica gel to giveN-2(4)-acetyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.23 (d, 1H, J=5.4 Hz), 7.03 (d, 1H, J=2.4 Hz),7.90-7.80 (m, 3H), 6.76 (m, 2H), 4.28 (bs, 4H), 2.10 (s, 3H); ¹⁹F NMR(CDCl₃): -42125; LCMS: ret. time: 27.94 min.; purity: 99%; MS (m/e): 439(MH⁺). 7.4.2N2,N4-Bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950244) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN2,N4-bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 17.03 min.; purity: 87.0%; MS (m/e): 478.89 (MH⁺).7.4.3N4-(3-N,N-Diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950245) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-(3-N,N-diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 19.27 min.; purity: 92.6%; MS (m/e): 521.01 (MH⁺).7.4.4N4-(3-N-Acetylaminophenyl)-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950246) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-[3-N-acetylaminophenyl]-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 18.89 min.; purity: 83.0%; MS (m/e): 520.97 (MH⁺).7.4.5N2,N4-Bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950247) N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN2,N4-bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 21.51 min.; purity: 91.8%; MS (m/e): 563.00 (MH⁺).Synthesis of Anilines 7.4.63-Chloro-4-(methoxycarbonylmethyleneoxy)nitrobenzene A dry reactionflask equipped with a magnetic stirring bar, reflux condenser and N2inlet was charged with a commercially available 2-chloro-4-nitrophenol(3.48 g, 20 mmol), K₂CO₃ (3.03 g, 21.81 mmol) and dry acetone (100 mL)under N₂ atmosphere. To this was added methyl bromoacetate (1.72 mL,18.18 mmol) and refluxed for 6 hours. Upon cooling, the reaction mixturewas diluted with ice-water (1 liter), solid obtained was filtered,washed with water (2 × 50 mL), and dried to give3-chloro-4-(methoxycarbonylmethyleneoxy)nitrobenzene. ¹H NMR (CDCl₃):δ8.33 (d, 1H, J=3 Hz), 8.13 (dd, 1H, J=2.7 and 9.3 Hz), 6.87 (d, 1H,J=9.3 Hz), 4.84 (s, 2H), 3.83 (s, 3H); LCMS: purity: 87%; MS (m/e): 287(M+ acetonitrile). 7.4.7 3-Chloro-4-(methoxycarbonylmethyleneoxy)anilineTo a solution of 3-chloro-4-(methoxycarbonylmethyleneoxy)nitrobenzene(1.00 g) in MeOH (50 mL) was added 0.050 g of 10% Pd/C, degassed andhydrogenated with a balloon filled with hydrogen (ca. 1 atmosphere) for2 hours. The reaction mixture was filtered through a pad of celite,concentrated and the resulting residue was then sonicated with ethylacetate and filtered. The filtrate upon concentration and drying under ahigh vacuum gave the 3-chloro-4-(methoxycarbonylmethyleneoxy)aniline. ¹HNMR (CDCl₃): δ6.79 (d, 1H, J=9 Hz), 6.73 (d, 1H, J=2.1 Hz), 6.50 (dd,1H, J=2.7 and 9.3 Hz), 4.60 (s, 2H), 3.80 (s, 3H); LCMS: purity: 87%; MS(m/e): 216 (MH⁺). 7.4.8 3-Chloro-4-(2-hydroxyethyleneoxy)nitrobenzene Adry reaction flask equipped with a magnetic stirring bar, N₂ inlet and arubber septum was charged with3-chloro-4-(methoxycarbonylmethyleneoxy)nitrobenzene (1.23 g, 5 mmol)and CH₂Cl₂ (50 mL) under N₂ atmosphere. The reaction solution was cooledto -78° C. and to it was added diisobutyllithiumaluminum hydridediisobutyl lithiumaluminum hydride (1.0 M in toluene, 15 mL, 15 mmol)over a period of 15 minutes. The reaction mixture was stirred at -78° C.for 2 hours and at room temperature for 1 hour, quenched with saturatedsolution of Rochelle′s salt and again stirred for 2 hours. Uponextraction with CH₂Cl₂, drying over anhydrous Na₂SO₄ and evaporation ofsolvent gave 3-chloro-4-(2-hydroxyethyleneoxy)nitrobenzene. ¹H NMR(CDCl₃): δ8.30 (d, 1H, J=3 Hz). 8.15 (dd, 1H, J=2.4 and 9 Hz), 7.02 (d,1H, J=8.7 Hz), 4.25 (t, 2H, J=4.8 Hz), 4.07 (m, 2H); LCMS: purity: 92%.7.4.9 3-Chloro-4-(2-hydroxyethyleneoxy)aniline In like manner to thepreparation of 3-chloro-4-(methoxycarbonylmethyleneoxy)aniline, thehydrogenation of 3-chloro-4(2-hydroxyethyleneoxy)nitrobenzene withballoon filled with hydrogen (ca. 1 atmosphere) in the presence of10%Pd/C as a catalyst gave 3-chloro-4-[2-hydroxyethyleneoxy)aniline. LCMS:MS (m/e): 187 (M⁺) 7.4.10 2-(N-Methylaminocarbonyl)-5-nitrobenzofuran Adry reaction flask equipped with a magnetic stirring bar, a rubberseptum and N₂ inlet was charged with 2-carboxy-5-nitrobenzofuran (2.07g, 10 mmol), N,N-dimethylformamide (DMF) (0.100 mL) and CH₂Cl₂ (50 mL)under N₂ atmosphere. The reaction mixture was cooled to 0° C. and to itwas added oxalyl chloride [(COCl)₂](2.65 mL, 30 mmol) over a period of10 minutes. The resulting mixture was stirred for 2 hours by the timethe 0° C. became room temperature and also the reaction became as aclear solution. It was concentrated and dried under high vacuum to yieldthe intermediate acid chloride. The resulting acid chloride was cooledto 0° C. and to it were added CH₂Cl₂ (50 mL), pyridine (2.96 mL, 30mmol) followed by methylamine hydrogen chloride salt (1.34 g, 20 mmol).Upon stirring for 24 hours at room temperature, the solvent was removedunder a reduced pressure and residue was suspended in water (200 mL).The solid formed was filtered, washed well with water and dried to give2-(N-methylaminocarbonyl)-5-nitrobenzofuran. ¹H NMR (CDCl₃): δ8.63 (d,1H, J=2.4 Hz), 8.33 (dd, 1H, J=2.4 and 9.3 Hz), 7.60 (d, 1H, J=7.8 Hz),7.59 (s, 1H), 3.07 (d, 3H, J=4.8 Hz); LCMS: purity: 98%; MS (m/e): 221(MH⁺). 7.4.11(±)-5-Amino-[2-(N-methylaminocarbonyl)-2,3-dihydro]benzofuran Asuspension of 2-(N-methylaminocarbonyl)-5-nitrobenzofuran (1.5 g), 10%Pd/C (1.5 g), Na₂SO₄ (1.5 g) in MeOH (200 mL) was hydrogenated at 55 PSIfor 3 days. The resulting solution was filtered through a pad of celite,concentrated to give(±)-5-amino-[2-(N-methylaminocarbonyl)-2,3-dihydro]benzofuran. ¹H NMR(CDCl₃): δ6.65 (m, 2H), 6.53 (m, 1H), 5.01 (dd, 1H, J=6.0 and 6.6 Hz),3.46 (dd, 1H, J=9.9 and 10.2 Hz), 3.18 (dd, 1H, J=6.0 and 4.2 Hz), 2.75(d, 3H). 7.4.12 2-(N,N-Dimethylaminocarbonyl)-5-nitrobenzofuran In likemanner to the preparation of2-(N-methylaminocarbonyl)-5-nitrobenzofuran, the reaction of2-carboxy-5-nitrobenzofuran with oxalyl chloride followed bydimethylamine hydrogen chloride salt afforded2-(N,N-dimethylaminocarbonyl)-5-nitrobenzofuran. ¹H NMR (CDCl₃): δ8.61(d, 1H, J=2.4 Hz), 8.31 (dd, 1H, J=2.4 and 9.3 Hz), 7.63 (d, 1H, J=9.3Hz), 7.40 9s, 1H), 3.35 (s, 3H), 3.17 (s, 3H); LCMS: purity: 97%; MS(m/e): 235 (MH⁺). 7.4.13(±)-5-Amino-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydro]benzofuran Inlike manner to the preparation of(±)-5-amino-[2-(N-methylaminocarbonyl)-2,3-dihydro]benzofuran, thehydrogenation of 2-(N,N-dimethylaminocarbonyl)-5-nitrobenzofuran yielded(±)-5-amino-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydro]benzofuran. ¹HNMR (DMSO-d₆): δ6.44 (m, 2H), 6.27 (dd, 1H, J=2.1 and 8.7 Hz), 5.42 (dd,1H, J=6.5 and 7.5 Hz), 4.54 (bd, J=5.4 Hz), 3.23 (m, 2H), 2.83 (s, 3H),2.82 (s, 3H); LCMS: purity: 70%; MS (m/e): 207 (MH⁺). 7.4.14 2-[(1R, 2S,5R)-Menthyloxycarbonyl)-5-nitrobenzofuran In like manner to thepreparation of 2-(N-methylaminocarbonyl)-5-nitrobenzofuran, the reactionof 2-carboxy-5-nitrobenzofuran with oxalyl chloride followed bytreatment with (1R, 2S, 5R)-(−)-menthol afforded 2-[(1R, 2S,5R)-menthyloxycarbonyl)-5-nitrobenzofuran. ¹H NMR (CDCl₃): δ8.63 (d, 1H,J=2.4 Hz), 8.35 (dd, J=2.4 and 8.7 Hz), 7.69 (d, 1H, J=9.3 Hz), 7.62 (s,1H), 5.00 (dt, 1H, J=4.8 and 10.5 Hz), 2.14 (bd, 1H, J=9.3 Hz), 1.95 (m,1H), 1.76 (m, 2H), 1.56 (m, 3H), 1.11 (m, 2H), 0.94 (d, 3H), 0.93 (d,3H), 0.82 (d, 3H, J=7.2 Hz); LCMS: purity: 99.67%. 7.4.155-Amino-[2(R)-(1R, 2S, 5R)-menthyloxycarbonyl-2,3-dihydro]benzofuran Inlike manner to the preparation of(±)-5-amino-[2-(N-methylamino)carbonyl]-2,3-dihydrobenzofuran, thehydrogenation of 2-[(1R, 2S, 5R)-menthyloxycarbonyl)-5-nitrobenzofuranyielded a diastereomeric mixture of 5-amino-[2-(1R, 2S,5R)-menthyloxycarbonyl-2,3-dihydro]benzofuran, from which the5-amino-[2(R)-(1R, 2S, 5R)-menthyloxycarbonyl-2,3-dihydro]benzofuran wasisolated as a crystalline diastereoisomer using solvent diffusionmethod^(*) (CH₂Cl₂:n-n-hexanes) of crystallization. ¹H NMR (CDCl₃):δ6.77 (bd, (1H), 6.73 (bs, 1H), 6.68 (dd, 1H, J=2.4 and 8.7 Hz), 5.11(dd, 1H, J=6.9 and 7.5 Hz), 4.76 (dt, 4.5 and 11.1 Hz), 3.49 (dd, 1H,J=9.9 and 10.5 Hz), 3.25 (dd, 1H, J=7.2 and 7.8 Hz), 1.99 (bd, 1H), 1.86(dpent, 1H, J=3.0 and 6.9 Hz), 1.70 (m, 1H), 1.66 (m, 1H), 1.46 (m, 2H),1.02 (m, 1H). 0.90 (d, 3H, 7.2 Hz), 0.89 (d, 3H, J=6.6 Hz), 0.75 (d, 3H,J=6.9 Hz); MS (m/e): 318 (MH⁺). ^(*) Solvent Diffusion Method: Theorganic molecule was dissolved in a minimum amount of CH₂Cl₂ and thecontainer was placed in a jar containing anti-solvent (n-hexanes), thelid was placed to avoid a loss of solvent and allowed to equilibratethem till the crysatalliztion was seen. The resulting crystals wereisolated by decantation of the solvent. 7.4.163,5-Dichloro-4-methoxyaniline To a solution of commercially available3,5-dichloro-4-methoxynitrobenzene (1.00 g, 4.5 mmol) in MeOH (100 mL)was added 10% Pd/C (0.100 g), degassed and hydrogenated using balloonfilled with hydrogen (ca. 1 atmosphere) for 2 hours. Upon filtrationthrough celite and concentration afforded 3,5-dichloro-4-methoxyaniline,which was isolated as 3,5-dichloro-4-methoxyaniline hydrogen chloridesalt by acidification with equivalent amount of HCl (4M, dioxane).Alternatively, this transformation was also achieved by stirring3,5-dichloro-4-methoxynitrobenzene (1.00 g, 4.5 mmol) with Na₂S₂O₄ (3.91g, 22.5 mmol) and K₂CO₃ (3.12 g, 22.5 mmol) in MeOH:H₂O (50 mL, each) atroom temperature for 24 hours. The extraction with ethyl acetatefollowed by removal of solvent gave 3,5-dichloro-4-methoxyaniline. LCMS:purity: 87%; MS (m/e): 233 (M+ acetonitrile). 7.4.174-Chloro-3-methoxyaniline To a solution of commercially available3,5-dichloro-4-methoxynitrobenzene (1.00 g, 4.5 mmol) in MeOH (100 mL)was added 10% Pd/C (0.100 g), degassed and hydrogenated using balloonfilled with hydrogen (ca. 1 atmosphere) for 2 hours. Upon filtrationthrough celite and concentration afforded 3,5-dichloro-4-methoxyaniline,which was isolated as 3,5-dichloro-4-methoxyaniline hydrogen chloridesalt by acidification with equivalent amount of HCl (4M, dioxane).Alternatively, this transformation was also achieved by stirring3,5-dichloro-4-methoxynitrobenzene (1.00 g, 4.5 mmol) with Na₂S₂O₄ (3.91g, 22.5 mmol) and K₂CO₃ (3.12 g, 22.5 mmol) in MeOH:H₂O (50 mL, each) atroom temperature for 24 hours. The extraction with ethyl acetatefollowed by removal of solvent gave 3,5-dichloro-4-methoxyaniline. LCMS:purity: 87%; MS (m/e): 233 (M+ acetonitrile). 7.4.184-Chloro-3,5-dimethylaniline To a suspension of commercially available4-chloro-3,5-dimethylnitrobenzene (0.185 g, 1 mmol) in EtOH: H₂O (5 mL,each) at room temperature was added ammonium chloride (0.265 g, 5 mmol)and iron powder (0.280 g, 5 mmol), stirred for 5 minutes at roomtemperature followed by 10 minutes at 60° C. Upon cooling to roomtemperature, the reaction mixture was filtered through a pad of celite,washed with ethanol and the filtrate was concentrated. The resultingresidue was diluted with water, saturated with sodium chloride andextracted with ethyl acetate. The organic solvent was removed under areduced pressure to afford the desired 4-chloro-3,5-dimethylaniline. ¹HNMR (CDCl₃): δ6.34 (s, 2H), 3.42 (bs, 2H), 2.20 (s, 6H); LCMS: purity:82%; MS: 156 (MH⁺). 7.4.19 3,4,5-Trimethylaniline In like manner to thehydrogenation of 3-(methoxycarbonylmethyleneoxy)aniline, thehydrogenation of commercially available 3,4,5-trimethylnitrobenzene gave3,4,5-trimethylaniline. LCMS: purity: 91%; MS (m/e): 136 (MH⁺).Synthesis of Mono-SNAr Products 7.4.20N2-Chloro-N4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineamineA mixture of 2,4-dichloro-5-fluoropyrimidine (0.305 g, 1.8 mmol) and3-chloro-4-(methoxycarbonylmethyleneoxy)aniline (0.332 g, 1.2 mmol) wasstirred in MeOH:H₂O (4 ml, each) at room temperature for 24 hours. Thereaction mixture was diluted with water (200 mL), sonicated for fewminutes, allowed to stand at room temperature for 30 minutes in order tosublime the residual 2,4-dichloro-5-fluoropyrimidine and the solidformed was filtered to obtainN2-chloro-N4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.07 (d, 1H, J=3 Hz), 7.66 (d, 1H, J=2.4 Hz), 7.53 (dd,1H, J=2.1 and 9.3 Hz), 6.90 (m, 2H), 4.72 (s, 2H), 3.82 (s, 3H); LCMS:purity: 80%; MS (m/e): 346 (MH⁺). 7.4.21N2-Chloro-N4-[3-chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-4-pyrimidineamineIn like manner to the preparation ofN2-chloro-N4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineamine,the reaction of 2,4-dichloro-5-fluoropyrimidine with3-chloro-4(2-hydroxyethyleneoxy)aniline gaveN2-chloro-N4-[3-chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-4-pyrimidineamine.LCMS: purity: 84%; MS (m/e): 318 (MH⁺). 7.4.222-Chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine Amixture of 2,4-dichloro-5-fluoropyrimidine (0.305 g, 1.8 mmol) and3-chloro-4-(methoxycarbonylmethyleneoxy)aniline (0.332 g, 1.2 mmol) wasstirred in MeOH:H₂O (4 ml, each) at room temperature for 24 hours. Thereaction mixture was diluted with water (200 mL), sonicated for fewminutes, allowed to stand at room temperature for 30 minutes in order tosublime the residual 2,4-dichloro-5-fluoropyrimidine and the solidformed was filtered to obtainN2-chloro-N4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.07 (d, 1H, J=3 Hz), 7.66 (d, 1H, J=2.4 Hz), 7.53 (dd,1H, J=2.1 and 9.3 Hz), 6.90 (m, 2H), 4.72 (s, 2H), 3.82 (s, 3H); LCMS:purity: 80%; MS (m/e): 346 (MH⁺). 7.4.23N2-Chloro-N4-[3-chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-4-pyrimidineamineIn like manner to the preparation ofN2-chloro-N4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineamine,the reaction of 2,4-dichloro-5-fluoropyrimidine with3-chloro-4(2-hydroxyethyleneoxy)aniline gaveN2-chloro-N4-[3-chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-4-pyrimidineamine.LCMS: purity: 84%; MS (m/e): 318 (MH⁺). 7.4.242-Chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine Inlike manner to the preparation ofN2-chloro-N4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineamine,the reaction of 2,4-dichloro-5-fluoropyrimidine with3-chloro-4(2-hydroxyethyleneoxy)aniline gaveN2-chloro-N4-[3-chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-4-pyrimidineamine.LCMS: purity: 84%; MS (m/e): 318 (MH⁺). 7.4.252-Chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine Inlike manner to the preparation ofN2-chloro-N4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineaminethe reaction of 2,4-dichloro-5-fluoropyrimidine with4-chloro-3-methoxyaniline gave2-chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-aminopyrimidine. LCMS:purity: 88%; MS (m/e): 288 (MH⁺). 7.4.262-Chloro-N4-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine Inlike manner to the preparation ofN2-chloro-N4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineaminethe reaction of 2,4-dichloro-5-fluoropyrimidine with3,5-dichloro-4-methoxyaniline hydrogen chloride salt gave2-chloro-N4-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ10.15 (s, 1H), 8.38 (d, 1H, J=3.4 Hz), 7.86 (d, 2H,J=3.0 Hz); LCMS: purity: 94%; MS (m/e): 321 (MH⁺). 7.4.27N4-(2-Aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine A mixture of2,6-diaminopyridine (0.109 g, 1 mmol) and2,4-dichloro-5-fluoropyrimidine (0.167 g, 1 mmol) in MeOH (2 mL) wasshaken in a sealed tube at 60° C. for 48 hours. Upon concentration, theresidue was absorbed on silica gel and chromatographed (silica gel;CH₂Cl₂ then 1% of 2N NH₃/MeOH in CH₂Cl₂) gaveN4-(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine. ¹H NMR(CD₃OD): δ8.16 (d, 1H, J=3.6 Hz), 7.46 (m, 2H), 6.32 (dd, 1H, J=3.9 and5.1 Hz); LCMS: purity: 80%; MS (m/e): 240 (MH⁺). 7.4.28N4-[2-(N-Acetylamino)pyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine Adry reaction flask equipped with a magnetic stirring bar, rubber septumand a N₂ inlet was charged withN4-(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine (0.120 g, 0.5mmol) and CH₂Cl₂. It was cooled to 0° C. and to it were added pyridine(0.100 mL, 1.0 mmol) followed by acetyl chloride (0.042 mL, 0.6 mmol)and stirred at room temperature for 2 hours. The reaction was quenchedwith water, extracted with CH₂Cl₂, dried over anhydrous Na₂SO₄ andsolvent was evaporated to yieldN4-[2-(N-acetylamino)pyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine.LCMS: purity: 80%; MS (m/e): 282 (MH⁺). 7.4.292-Chloro-5-fluoro-N4-[2-(N-methylaminocarbonyl)aminopyrid-6-yl]-2,4-pyrimidineamineTo a suspension ofN4-(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine (0.06 g, 0.25mmol) in THF (1 mL) at 0° C. were added triethylamine (0.050 mL, 0.35mmol), 4-N,N-dimethylaminopyridine (0.5 mg) followed by triphosgene(0.037 g, 0.125 mmol). The resulting reaction mixture was then stirredat room temperature for 1 hour, quenched with an aqueous solution ofmethylamine (40%, 2 mL), shaken for 5 minutes and diluted with water.The aqueous solution was extracted with ethyl acetate, solvent wasevaporated and the residue was chromatographed (silica gel; CH₂Cl₂ then2-5% of 2M NH₃/MeOH in CH₂Cl₂) to yield2-chloro-5-fluoro-N4-[2-(N-methylaminocarbonyl)aminopyrid-6-yl]-2,4-pyrimidineamine.¹H NMR (DMSO-d₆): δ10.34 (s, 1H), 9.34 (s, 1H), 8.72 (m, 1H), 8.45 (d,1H, J=3.6 Hz), 7.68 (t, 1H, J=8.1 Hz), 7.52 (d, 1H, J=7.8 Hz), 6.89 (d,1H, J=8.1 Hz), 2.77 (d, 3H, J=3.3 Hz); LCMS: purity: 88%; MS (m/e): 297(MH⁺). Synthesis of Bis-SNAr Products 7.4.30N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R927042) A sealed tube was charged with2-chloro-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine (0.109g, 0.38 mmol), 3-[N-(methylamino)carbonylmethyleneoxy]aniline (0.068 g,0.38 mmol) and MeOH (2 mL) and then heated at 100° C. for 24 hours. Uponcooling to the room temperature, it was diluted with water, acidifiedand the solid obtained was filtered dried and purified by columnchromatography (silica gel, CH₂Cl₂ then 2N NH₃/MeOH upto 2-5% in CH₂Cl₂)to giveN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.Alternatively, the resulting reaction was diluted with ethyl acetate,the solid was isolated by using centrifuge technique and subjected forthe purification as above. By doing this, the most of the unreactedmono-SNAr product and second aniline go into ethyl acetate keeping thedesired bis-SNAr product as a solid. ¹H NMR (DMSO-d₆): δ9.89 (bs, 1H),9.66 (bs, 1H), 8.20 (d, 1H, J=4.8 Hz), 7.95 (bd, 1H), 7.48 (m, 2H), 7.33(d, 1H, J=9.3 Hz), 7.26 (bs, 1H), 7.17 (m, 2H), 6.57 (bd, 1H, J=7.8 Hz),4.34 (s, 2H), 3.72 (s, 3H), 2.66 (s, 3H); LCMS: purity: 97%; MS (m/e):432 (MH⁺). 7.4.31N4-(3-Chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineIn like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-chloro-N4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3-[N-(methylamino)carbonylmethyleneoxy]aniline gaveN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: purity: 81%; MS (m/e): 490 (MH⁺). 7.4.32N4-[3-Chloro-4-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R927043) A sealed tube charged withN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(0.123 g, 0.25 mmol), methylamine hydrogen chloride salt (0.084 g, 1.25mmol), diisopropylethyl amine (0.217 mL, 1.25 mmol) and MeOH (4 mL) andheated at 100° C. for 24 hours. Upon cooling to the room temperature, itwas diluted with water (50 mL), extracted with ethyl acetate (3 × 25 mL)and the organic solvent was evaporated. The resulting residue waspurified by column chromatography (silica gel, CH₂Cl₂ then 2N NH₃/MeOHupto 2% in CH₂Cl₂) to giveN4-[3-chloro-4-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.35 (bs, 1H), 9.24 (bs, 1H), 8.09 (d, 1H, J=3.6 Hz),7.94 (bd, 1H), 7.87 (bd, 1H, J=4.2 Hz), 7.83 (t, 1H, J=2.4 Hz). 7.72 (m,1H), 7.29 (m, 2H), 7.11 (t, 1H, J=8.4 Hz), 6.99 (d, 1H, J=8.7 Hz), 6.47(dd, 1H, J=1.8 and 10.5 Hz), 4.53 (s, 2H), 4.33 (s, 2H), 2.66 (d, 3H,J=4.8 Hz), 2.63 (d, 3H, J=4.8 Hz); LCMS: purity: 92%; MS (m/e): 489(MH⁺). 7.4.33N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R927047) In like manner to the preparartion ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN2-chloro-N4-[3-chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-4-pyrimidineaminewith 3-[N-(methylamino)carbonylmethyleneoxy]aniline gaveN4-[3-chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 9.22 (s, 1H), 8.08 (d, 1H, J=3.6 Hz),7.94 (m, 1H), 7.80 (d, 1H, J=2.4 Hz), 7.68 (dd, 1H, J=2.4 and 8.7 Hz),7.31 (bs, 1H), 7.29 (d, 1H, J=1.2 Hz), 7.10 (m, 2H), 6.46 (m, 1H), 4.34(s, 2H), 4.04 (t, 2H, J=5.4 Hz), 3.71 (t, 2H, J=5.1 Hz), 2.62 (d, 3H,J=4.8 Hz); LCMS: purity: 89%; MS (m/e): 462 (MH⁺) 7.4.34N4-(3,5-Dichloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R927057) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3-[N-(methylamino)carbonylmethyleneoxy]aniline gaveN4-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.80 (s, 1H), 9.60 (bs, 1H), 8.21 (d, 1H, J=3.6 Hz),7.98 (bd, 1H), 7.90 (m, 2H), 7.20 (m, 3H), 6.56 (bd, 1H), 4.36 (s, 1H),3.78 (s, 3H), 2.63 (d, 3H, J=3.3 Hz); LCMS: purity: 96%; MS (m/e): 394(MH⁺). 7.4.35N4-(2-Aminopyrid-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R927080) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine with3-[N-(methylamino)carbonylmethyleneoxy]aniline gaveN4-(2-aminopyrid-6-yl)-5-fluoro-N2-[3-(N-36methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.96 (d, 1H, J=3.0 Hz), 7.58 (d, 1H, J=7.8 Hz), 7.40(m, 2H), 7.17 (m, 2H), 6.60 (m, 1H), 6.27 (bd, 1H, J=7.8 Hz), 4.47 (s,2H), 2.82 (s, 3H); LCMS: purity: 100%; MS (m/e): 384 (MH⁺). 7.4.36N4-[2-(N-Acetylamino)pyrid-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R927093) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-[2-(N-acetylamino)pyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineaminewith 3-[N-(methylamino)carbonylmethyleneoxy]aniline gaveN4-[2-(N-acetylamino)pyrid-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.22 (s, 1H), 9.35 (s, 1H), 9.05 (s, 1H), 8.18 (d,1H, J=3.3 Hz), 7.96 (m, 1H), 7.75 (s, 2H), 7.38 (bs, 1H), 7.29 (bd, 1H,J=8.4 Hz), 7.11 (t, 1H, J=8.4 Hz), 6.49 (bdd, 1H, J=8.4 Hz), 4.37 (s,2H), 2.65 (d, 3H), 2.18 (s, 3H); LCMS: purity: 80%; MS (m/e): 426 (MH⁺)7.4.37N4-(3-Chloro-4-methoxyphenyl)-N2-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927044) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with3,5-dichloro-4-hydroxyaniline gaveN4-(3-chloro-4-methoxyphenyl)-N2-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.46 (s, 1H), 9.34 (s, 1), 9.22 (s, 1H), 8.09 (d, 1H,J=3.6 Hz), 7.66 (m, 1H), 7.63 (m, 2H), 7.10 (d, 1H, J=9.3 Hz), 3.82 (s,3H); LCMS: purity: 100%; MS (m/e): 430 (MH⁺). 7.4.38N4-(3-Chloro-4-trifluoromethoxyphenyl)-N2-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927046) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3,5-dichloro-4-hydroxyaniline gaveN4-(3-chloro-4-trifluoromethoxyphenyl)-N2-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.70 (s, 1H), 9.54 (s, 1H), 9.35 (s, 1H), 8.20 (d,1H, J=3.6 Hz), 8.01 (t, 1H, J=3 Hz), 7.85 (m, 1H), 7.65 (s, 1H), 7.64(s, 1H), 7.46 (bdd, 1H, J=8.1 Hz); LCMS: purity: 97%; MS (m/e): 484(MH⁺). 7.4.39N2-(3,5-Dichloro-4-hydroxyphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927048) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3,5-dichloro-4-hydroxyaniline gaveN2-(3,5-dichloro-4-hydroxyphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.96 (s, 1H), 9.58 (s, 1H), 9.47 (s, 1H), 9.27 (s,1H), 8.13 (d, 1H, J=3.6 Hz), 7.65 (s, 2H), 7.38 (m, 2H), 7.25 (d, 1H,J=9 Hz); LCMS: purity: 92%; MS (m/e): 472 (MH⁺). 7.4.40N2-(3,5-Dichloro-4-hydroxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927051) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-3-oxo-6-yl)-5-fluoro-4-pyrimidineaminewith 3,5-dichloro-4-hydroxyaniline gaveN2-(3,5-dichloro-4-hydroxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.61 (s, 1H), 9.45 (s, 1H), 9.34 (s, 1H), 9.18 (s,1H), 8.07 (bs, 1H), 7.66 (bs, 2H), 7.23 (bd, 1H, J=8.1 Hz), 7.12 (s,1H), 6.88 (d, 1H, J=8.4 Hz), 1.39 (s, 6H); LCMS: purity: 100%; MS (m/e):464 (MH⁺). 7.4.41N4-(3-Chloro-4-methoxyphenyl)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927054) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidineamine with3,5-dichloro-4-methoxyaniline hydrogen chloride salt gaveN4-(3-chloro-4-methoxyphenyl)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.46 (s, 1H), 9.42 (s, 1H), 8.12 (d, 1H, J=3 Hz),7.73 (s, 2H), 7.65 (d, 1H, J=2.4 Hz), 7.60 (dd, 1H, J=2.1 and 8.7 Hz),7.12 (d, 1H, J=8.7 Hz), 3.84 (s, 3H), 3.73 (s, 3H); LCMS: purity: 97%;MS (m/e): 443 (MH⁺). 7.4.42N4-(3-Chloro-4-trifluoromethoxyphenyl)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927055) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidineaminewith 3,5-dichloro-4-methoxyaniline hydrogen chloride salt gaveN4-(3-chloro-4-trifluoromethoxyphenyl)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.77 (s, 1H), 9.59 (s, 1H), 8.23 (d, 1H, J=3.9 Hz),8.00 (d, 1H, J=2.1 Hz), 7.84 (dd, 1H, J=2.7 and 9.0 Hz), 7.75 (d, 2H,J=1.5 Hz), 7.50 (bd, 1H, J=9.3 Hz), 3.74 (s, 3H); LCMS: purity: 75%; MS(m/e): 499 (MH⁺). 7.4.43N4-(3,4-Dichlorophenyl)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927058) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidineamine with3,5-dichloro-4-methoxyaniline hydrogen chloride salt gaveN4-(3,4-dichlorophenyl)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 93%; MS (m/e): 449 (MH⁺). 7.4.44N2-(3,5-Dichloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927056) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3,5-dichloro-4-methoxyaniline hydrogen chloride salt gaveN2-(3,5-dichloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 92%; MS (m/e): 478 (MH⁺). 7.4.45N2-(3,5-Dichloro-4-methoxyphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927061) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3,5-dichloro-4-methoxyaniline hydrogen chloride salt gaveN2-(3,5-dichloro-4-methoxyphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-3-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.95 (s, 1H), 9.64 (s, 1H), 9.50 (s, 1H), 8.16 (d,1H, J=3.6 Hz), 7.74 (s, 2H), 7.38 (m, 2H), 7.26 (m, 1H), 3.71 (s, 3H);LCMS: purity: 92%; MS (m/e): 486 (MH⁺). 7.4.46N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-3-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927050) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-3-6-yl)-5-fluoro-4-pyrimidineaminewith 3,5-dimethoxyaniline gaveN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.53 (s, 1H), 9.31 (s, 1H), 8.99 (s, 1H), 8.06 (d,1H, J=3.9 Hz), 7.26 (m, 2H0, 6.93 (s, 1H), 6.92 (s, 1H), 6.85 (d, 1H,J=8.7 Hz), 6.03 (t, 1H, J=2.4 Hz), 3.61 (s, 6H), 1.39 (s, 6H); LCMS:purity: 92%; MS (m/e): 440 (MH⁺). 7.4.47N4-(3,4-Dichlorophenyl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927060) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine with3,5-dimethoxyaniline gaveN4-(3,4-dichlorophenyl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.60 (s, 1H), 9.26 (s, 1H), 8.16 (d, 1H, J=3.6 Hz),8.08 (t, 1H, J=3.0 Hz), 7.85 (m, 1H), 7.51 (d, 1H, J=9.0 Hz), 6.89 (t,2H, J=2.4 Hz), 6.08 (t, 1H, J=2.4 Hz), 3.64 (s, 6H); LCMS: purity: 96%;MS (m/e): 409 (MH⁺). 7.4.48N4-(3-Chloro-4-methoxyphenyl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927066) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with3,5-dimethoxyaniline gaveN4-(3-chloro-4-methoxyphenyl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 9.14 (s, 1H), 8.08 (d, 1H, J=3.3 Hz),7.74 (m, 2H), 7.08 (d, 1H, J=8.7 Hz), 6.90 (d, 2H, J=2.1 Hz) 6.05 (t,1H, J=2.4 Hz), 3.84 (s, 3H), 3.63 (s, 6H); LCMS: purity: 100%; MS (m/e):405 (MH⁺). 7.4.49N4-(3-Chloro-4-trifluoromethoxyphenyl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927067) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineaminewith 3,5-dimethoxyaniline gaveN4-(3-chloro-4-trifluoromethoxyphenyl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.67 (s, 1H), 9.28 (s, 1H), 8.18 (d, 1H, J=3.6 Hz),8.09 (t, 1H, J=1.2 Hz), 7.91 (dd, 1H, J=2.7 and 9.0 Hz), 7.45 (bd, 1H,J=9.0 Hz), 6.89 (d, 2H, J=1.8 Hz), 6.08 (s, 1H), 3.64 (s, 6H); LCMS:purity: 97%; MS (m/e): 459 (MH⁺). 7.4.50N4-[2-Aminopyrid-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927077) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine with3,5-dimethoxyaniline gaveN4-[2-aminopyrid-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.00 (bs, 1H), 7.75 (bd, 1H), 7.45 (t, 1H), 7.30 (bs,1H), 7.25 (bs, 1H), 7.05 (bs, 1H), 6.80 (bs, 2H), 6.20 (m, 2H), 4.35(bs, 2H), 3.75 (s, 6H); LCMS: purity: 91%; MS (m/e): 357 (MH⁺). 7.4.51N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediamine(R927089) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(indol-6-yl)-4-pyrimidineamine with3,5-dimethoxyaniline gaveN2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.60 (bs, 1H), 8.43 (s, 1H), 7.90 (d, 1H, J=3.3 Hz),7.56 (d, 1H, J=8.4 Hz), 7.22 (m, 2H), 6.95 (bd, 1H), 6.88 (dd, 1H, J=1.8and 8.4 Hz), 6.82 (s, 1H), 6.81 (s, 1H), 6.52 (bt, 1H), 6.25 (t, 1H,J=1.8 Hz), 3.74 (s, 6H); LCMS: purity: 97%; MS (m/e): 380 (MH⁺). 7.4.52N4-[2-(N-Acetylamino)pyrid-6-yl]-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927096) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-[2-(N-acetylamino)pyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineaminewith 3,5-dimethoxyaniline gaveN4-[2-(N-acetylamino)pyrid-6-yl]-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 82%; MS (m/e): 399 (MH⁺). 7.4.53N2-(3,5-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927064) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3,5-dichloroaniline gaveN2-(3,5-dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.61 (s, 1H), 9.55 (s, 1H), 9.42 (s, 1H), 8.13 (d,1H, J=3.6 Hz), 7.74 (s, 1H), 7.73 (s, 1H), 7.21 (m, 1H), 7.11 (s, 1H),6.98 (s, 1H), 6.90 (d, 1H, J=8.7 Hz), 1.38 (s, 6H); LCMS: purity: 91%;MS (m/e): 448 (MH⁺). 7.4.54N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R927065) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3-methoxy-5-trifluoromethylaniline gaveN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.57 (s, 1H), 9.41 (s, 1H), 9.38 (s, 1H), 8.11 (d,1H, J=3.6 Hz), 7.65 (s, 1H), 7.59 (s, 1H), 7.30 (m, 1H), 7.18 (s, 1H),6.85 (d, 1H, J=8.7 Hz), 6.69 (s, 1H), 3.70 (s, 3H), 1.39 (s, 6H); LCMS:purity: 98%; MS (m/e): 478 (MH⁺). 7.4.55N2-(2,6-Dimethoxypyrid-3-yl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927068) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3-amino-2,6-dimethoxypyridine gaveN2-(2,6-dimethoxypyrid-3-yl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.56 (s, 1H), 9.28 (s, 1H), 7.87 (m, 2H), 7.67 (s,1H), 7.34 (s, 1H), 7.16 (dd, 1H, J=2.1 and 8.4 Hz), 6.79 (d, 1H, J=8.7Hz), 6.26 (d, 1H, J=8.4 Hz), 3.87 (s, 3H), 3.82 (s, 3H), 1.39 (s, 6H);LCMS: purity: 97%; MS (m/e): 441 (MH⁺). 7.4.56N2-(2,6-Dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927069) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3,5-dimethylaniline gaveN2-(2,6-dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.74 (s, 1H), 10.40 (bs, 1H), 10.10 (bs, 1H), 8.25(bd, 1H), 7.24 9dd, 1H, J=2.4 and 8.1 Hz), 7.14 (s, 1H), 7.09 (bs, 2H),6.92 (d, 1H, J=9.0 Hz), 6.68 (bs, 1H), 2.16 (s, 6H), 1.40 (s, 6H); LCMS:purity: 95%; MS (m/e): 408 (MH⁺). 7.4.57N4-(2-Aminopyrid-6-yl)-N2-(2,6-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R927078) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine with3,5-dimethylaniline gaveN4-(2-aminopyrid-6-yl)-N2-(2,6-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.33 (bs, 1H), 7.78 (t, 1H, J=8.7 Hz), 7.29 (bs, 2H),6.77 (bd, 1H, J=5.4 Hz), 6.61 (bs, 1H), 6.47 (d, 1H, J=8.7 Hz), 2.22 (s,6H); LCMS: purity: 100%; MS (m/e): 325 (MH⁺). 7.4.58N4-(3,4-Dichlorophenyl)-N2-(2,6-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R927079) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine with3,5-dimethylaniline gaveN4-(3,4-dichlorophenyl)-N2-(2,6-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.57 (s, 1H), 9.18 (s, 1H), 8.16 (d, 1H, J=3.6 Hz),8.04 (d, 1H, J=2.7 Hz), 7.81 (dd, 1H, J=2.7 and 9.3 Hz), 7.52 (d, 1H,J=9.0 Hz), 7.22 (s, 2H), 6.54 (d, 1H, J=1.2 Hz), 2.17 (s, 6H); LCMS:purity: 92%; MS (m/e): 377 (M⁺). 7.4.59N2-(2,6-Dimethylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927086) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3,5-dimethylaniline gaveN2-(2,6-dimethylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.11 (s, 1H), 9.01 (s, 1H), 8.02 (d, 1H, J=3.9 Hz),7.26 (m, 3H), 7.18 (m, 1H), 6.78 (d, 1H, J=8.7 Hz), 6.49 (bs, 1H), 4.21(s, 4H), 2.16 (s, 6H); LCMS: purity: 97%; MS (m/e): 367 (MH⁺). 7.4.60N2-(2,6-Dimethylphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediamine(R927088) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(indol-6-yl)-4-pyrimidineamine with3,5-dimethylaniline gaveN2-(2,6-dimethylphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.12 (bs, 1H), 7.95 (bs, 1H), 7.92 (d, 1H, J=3.3 Hz),7.60 (d, 1H, J=8.7 Hz), 7.19 (t, 1H, J=2.7 Hz), 7.15 (s, 2H), 7.07 (dd,1H. J=1.5 and 8.1 Hz), 6.93 (s, 1H), 6.86 (bs, 1H), 6.65 (s, 1H), 6.54(m, 1H), 2.19 (s, 6H); LCMS: purity: 100%; MS (m/e): 348 (MH⁺). 7.4.61N4-[2-(N-Acetylamino)pyrid-6-yl]-N2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R927092) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-[2-(N-acetylamino)pyrid-6-yl]-2-chloro-5-fluoro-2,4-pyrimidineaminewith 3,5-dimethylaniline gaveN4-[2-(N-acetylamino)pyrid-6-yl]-N2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.23 (s, 1H), 9.18 (s, 1H), 8.99 (bs, 1H), 8.17 (m,1H), 7.73 (m, 2H), 7.28 (s, 1H), 7.25 (s, 2H), 6.55 (m, 1H), 2.20 (s,3H), 2.17 (s, 3H); LCMS: purity: 80%; MS (m/e): 367 (MH⁺). 7.4.62N2-(3,5-Dimethylphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylaminopyrid-6-yl]-2,4-pyrimidinediamine(R927098) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-[2-(N-methylamino)carbonylaminopyrid-6-yl]-2,4-pyrimidineaminewith 3,5-dimethylaniline gaveN2-(3,5-dimethylphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylaminopyrid-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.73 (s, 1H), 9.26 (s, 1H), 9.21 (s, 1H), 8.77 (bs,1H0, 8.21 (d, 1H, J=3.3 Hz), 7.79 (d, 1H, J=7.5 Hz), 7.57 (t, 1H, J=7.8Hz), 7.27 (s, 2H), 6.62 (d, 1H, J=8.4 Hz), 6.55 (s, 1H), 2,74 (d, 3H,J=4.2 Hz), 2.20 (s, 6H); LCMS: purity: 100%; MS (m/e): 382 (MH⁺). 7.4.63N2-(3,5-Dimethylphenyl)-5-fluoro-N4-[1-(N-methylamino)carbonylindol-6-yl]-2,4-pyrimidinediamine(R927099) In like manner to the preparation of2-chloro-5-fluoro-N4-[2-(N-methylamino)carbonylaminopyrid-6-yl]-2,4-pyrimidineamine,the reaction ofN2-(3,5-dimethylphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediaminewith triphosgene gaveN2-(3,5-dimethylphenyl)-5-fluoro-N4-[1-(N-methylaminocarbonyl)indol-6-yl)-2,4-pyrimidinediamine.LCMS: purity: 92%; MS (m/e): 405 (MH⁺). 7.4.64N4-(2-Aminopyrid-6-yl)-N2-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927081) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine with3-chloro-4-trifluoromethoxyaniline gaveN4-(2-aminopyrid-6-yl)-N2-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.66 (s, 1H), 8.94 (s, 1H), 8.16 (d, 1H, J=3.0 Hz),8.12 (bd, 1H), 7.65 (bd, 1H, J=9.0 Hz), 7.39 (m, 2H), 7.22 (m. 1H), 6.20(d, 1H, J=7.8 Hz), 5.84 (bs, 2H); LCMS: purity: 95%; MS (m/e): 415(MH⁺). 7.4.65N2-(3-Chloro-4-trifluoromethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927085) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-chloro-4-trifluoromethoxyaniline gaveN2-(3-chloro-4-trifluoromethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.1H NMR (DMSO-d₆): d 9.56 (s, 1H), 9.28 (s, 1H0, 8.10 (d, 1H, J=3.9 Hz),8.05 (d, 1H, J=2.4 Hz), 7.60 (dd, 1H, J=2.7 and 9.0 Hz), 7.34 (dd, 1H,J=1.2 and 9.0 Hz), 7.24 (d, 1H, J=2.4 Hz), 7.12 (dd, 1H, J=2.4 and 8.7Hz), 6.81 (d, 1H, J=8.4 Hz), 4.22 (s, 4H); LCMS: purity: 90%; MS (m/e):457 (MH⁺). 7.4.66N4-(2-Aminopyrid-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927082) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine with3-chloro-4-methoxyaniline gaveN4-(2-aminopyrid-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.23 (s, 1H), 8.68 (s, 1H), 8.09 (d, 1H, J=3.3 Hz),7.86 (d, 1H, J=2.4 Hz), 7.46 (bd, 1H, J=9.6 Hz), 7.34 (m, 2H), 7.02 (d,1H, J=9.0 Hz), 6.17 9d, 1H, J=7.2 Hz), 5.80 (m, 2H), 3.78 (s, 3H); LCMS:purity: 100%; MS (m/e): 361 (MH⁺). 7.4.67N2-(3-Chloro-4-methoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927084) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with3-chloro-4-methoxyaniline gaveN2-(3-chloro-4-methoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.15 (s, 1H), 9.12 (s, 1H), 8.02 (d, 1H, J=3.9 Hz),7.80 (d, 1H, J=2.4 Hz), 7.48 (dd, 1H, J=2.4 and 6.3 Hz), 7.26 (d, 1H,J=2.4 Hz), 7.16 (dd, 1H, J=2.7 and 9.3 Hz), 7.00 (d, 1H, J=8.7 Hz), 6.79(d, 1H, J=8.7 Hz), 4.22 (bs, 4H), 3.78 (s, 3H); LCMS: purity: 96%; MS(m/e): 403 (MH⁺). 7.4.68N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediamine(R927091) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of 2-chloro-5-fluoro-N4-(indol-6-yl)-4-pyrimidineamine with3-chloro-4-methoxyaniline gaveN2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ8.25 (bs, 1H), 8.03 (bs, 1H), 7.89 (d, 1H, J=3.3 Hz),7.82 (d, 1H, J=2.7 Hz), 7.59 (d, 1H, J=8.4 Hz), 7.20 (m, 1H), 7.15 (d,1H, J=2.4 Hz), 7.02 (bs, 1H), 6.96 (dd, 1H, J=2.1 and 8.4 Hz), 6.92 (m,1H), 6.84 (d, 1H, J=8.7 Hz), 6.52 (m, 1H), 3.89 (s, 3H); LCMS: purity:97%; MS (m/e): 380 (MH⁺). 7.4.69N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-[1-(N-methylaminocarbonyl)indol-6-yl]-2,4-pyrimidinediamine(R927100) In like manner to the preparation of2-chloro-5-fluoro-N4-[2-(N-methylaminocarbonyl)aminopyrid-6-yl]-2,4-pyrimidineamine,the reaction ofN2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(indol-6-yl)-2,4-pyrimidinediaminewith triphosgene followed by methylamine quench gaveN2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-[N1-(N-methylaminocarbonyl)indol-6-yl]-2,4-pyrimidinediamine.LCMS: purity: 88%; MS (m/e): 441 (MH⁺). 7.4.70N4-(2-Aminopyrid-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R927083) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine with3-hydroxyaniline gaveN4-(2-aminopyrid-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.17 (s, 1H), 9.13 (s, 1H), 8.62 (s, 1H), 8.08 (d,1H, J=3.0 Hz), 7.42 (m, 1H), 7.35 (t, 1H, J=7.8 Hz), 7.18 (bs, 1H), 7.14(bd, 1H, J=7.2 Hz), 6.98 (t, 1H, J=7.8 Hz), 6.31 (dd, 1H, J=1.2 and 6.9Hz), 6.17 (d, 1H, J=7.5 Hz), 5.77 (m. 1H); LCMS: purity: 100%; MS (m/e):313 (MH⁺). 7.4.71N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2[1-(N-methylaminocarbonyl)indol-6-yl]-2,4-pyrimidinediamine(R927094) In like manner to the preparation of2-chloro-5-fluoro-N4-[2-(N-methylaminocarbonyl)aminopyrid-6-yl]-2,4-pyrimidineamine,the reaction ofN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediaminewith triphosgene followed by methylamine quench gaveN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2[1-(N-methylaminocarbonyl)indol-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): d 11.09 (s, 1H), 9.70 (d, 1H, 4.2 Hz), 9.49 (s, 1H),8.18 (d, 1H, J=3.3 Hz), 7.54 (d, 1H, J=8.4 Hz), 7.41 (t, 1H, J=2.7 Hz),7.30 (d, 1H, J=2.7 Hz), 7.15 (s, 1H), 6.81 (dd, 1H, J=2.7 and 9.0 Hz),6.72 (dd, 1H), J=1.8 and 8.1 Hz), 6.54 (s, 1H), 5.74 (d, 1H, J=9.6 Hz),3.62 (s, 3H), 2.77 (d, 3H, J=4.5 Hz); LCMS: purity: 99%; MS (m/e): 441(MH⁺). 7.4.72N2-(3-Chloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927097) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3-chloro-4-methoxyaniline gaveN2-(3-chloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-3-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.60 (s, 1H), 9.31 (s, 1H0, 9.08 (s, 1H), 8.04 (d,1H, J=3.6 Hz), 7.81 (d, 1H, J=3.3 Hz), 7.45 (dd, 1H, J=2.7 and 9.3 Hz),7.23 (dd, 1H, J=2.1 and 8.7 Hz), 7.16 (d, 1H, J=2.4 Hz), 6.93 (d, 1H,J=9.0 Hz), 6.89 (d, 1H, J=8.4 Hz), 3.76 (s, 3H), 1.40 (s, 9H); LCMS:purity: 97%; MS (m/e): 444 (MH⁺). 7.4.73N4-(3,4-Dichlorophenyl)-N2-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927059) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4pyrimidineamine with6-amino-2,2-dimethyl-3-oxo-4H-benz[1,4]oxazine gaveN4-(3,4-dichlorophenyl)-N2-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.64 (s, 1H), 10.10 (s, 1H), 9.72 (s, 1H), 8.22 (d,1H, J=3.9 Hz), 8.10 (bs, 1H), 7.74 (bd, 1H, J=9.0 Hz), 7.52 (d, 1H, J=9Hz); LCMS: purity: 89%; MS (m/e): 448 (MH⁺). 7.4.74N2-(4-Chloro-3,5-dimethylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R927117) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with4-chloro-3,5-dimethylaniline gaveN2-(4-chloro-3,5-dimethylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.16 (bs, 2H), 8.04 (d, 1H, J=3.6 Hz), 7.45 (s, 2H),7.25 (m, 1H), 6.80 (d, 1H, J=8.7 Hz), 4.21 (bs, 4H), 2.22 (s, 6H); LCMS:purity: 91%; MS (m/e): 401 (MH⁺). 7.4.75N2-(4-Chloro-3,5-dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R927118) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 4-chloro-3,5-dimethylaniline gaveN2-(4-chloro-3,5-dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.62 (s, 1H), 9.32 (s, 1H), 9.11 (s, 1H), 8.06 (d,1H, J=3.9 Hz), 7.46 (s, 2H), 7.26 (dd, 1H, J=2.4 and 8.7 Hz), 7.18 (m,1H), 6.89 (d, 1H, J=8.7 Hz), 2.20 (s, 6H), 1.40 (s, 6H); LCMS: purity:99%; MS (m/e): 441 (M⁺). 7.4.76(±)-N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(N-methylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927049) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith (±)-5-amino-2-(N-methylaminocarbonyl)-2,3-dihydrobenzofuran gave(±)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(N-methylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.96 (s, 1H), 9.48 (s, 1H), 8.92 (s, 1H), 8.06 (d,1H, J=3.6 Hz), 8.01 (d, 1H, J=4.5 Hz), 7.56 (m, 1H), 7.49 (bs, 1H), 7.40(s, 1H), 7.23 (m, 2H), 6.67 (d, 1H, J=8.7 Hz), 5.04 (dd, 1H, J=5.7 and6.6 Hz), 3.58 (dd, 1H), 3.11 (dd, 1H, J=5.7 and 6.6 Hz), 2.59 (d, 3H,J=4.5 Hz); LCMS: purity: 98%; MS (m/e): 487 (MH⁺). 7.4.77(±)-N4-(3-Chloro-4-methoxyphenyl)-N2-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927052) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with(±)-5-amino-2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran gave(±)-N4-(3-chloro-4-methoxyphenyl)-N2-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.24 (s, 1H), 8.98 (s, 1H), 8.01 (d, 1H, J=3.3 Hz),7.74 (d, 1H, J=2.4 Hz), 7.64 (dd, 1H, J=2.1 and 9.0 Hz), 7.49 (s, 1H),7.19 (d, 1H, 8.7 Hz), 7.10 (d, 1H, J=8.7 Hz), 6.64 (d, 1H, J=8.7 Hz),5.54 (dd, 1H, J=8.7 and 7.8 Hz), 3.84 (s, 3H), 3.30 (m, 2H), 3.08 (s,3H), 2.86 (s, 3H); LCMS: purity: 93%; MS (m/e): 458 (MH+). 7.4.78(±)-N4-(3-Chloro-4-trifluoromethoxyphenyl)-N2-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927053) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineaminewith (±)-5-amino-2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofurangave(±)-N4-(3-chloro-4-trifluoromethoxyphenyl)-N2-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.59 (s, 1H), 9.10 (s, 1H), 8.12 (d, 1H, J=3.6 Hz),8.09 (s, 1H), 7.83 (bd, 1H, J=8.7 Hz), 7.48 (m, 2H), 7.20 (bd, 1H,J=J=8.4 Hz), 6.67 (d, 1H, J=8.4 Hz), 5.58 (d, 1H, J=8.1 Hz), 3.30 (m,2H), 3.08 (s, 3H), 3.86 (s, 3H); LCMS: purity: 96%; MS (m/e): 512 (MH⁺).7.4.79(±)-N4-(3-Chloro-4-methoxyphenyl)-N2-[2-(N-methylaminomethylene)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927045) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine,the reduction of(±)-N4-(3-chloro-4-methoxyphenyl)-N2-[2-(N-methylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediaminewith borane:methyl sulfide gave(±)-N4-(3-chloro-4-methoxyphenyl)-N2-[2-(N-methylaminomethylene)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.22 (s, 1H), 8.92 (s, 1H), 8.01 (d, 1H, J=3.6 Hz),7.78 (t, 1H, J=3.0 Hz), 7.64 (m, 1H), 7.43 (bs, 1H), 7.16 (dd, 1H, J=2.4and 10.5 Hz), 7.08 (d, 1H, J=8.7 Hz), 6.57 (d, 1H, J=8.1 Hz), 4.77 (m,1H), 3.82 (s, 3H), 3.11 (dd, 1H, J=9.3 and 8.7 Hz), 2.85 (dd, 1H, J=7.5Hz), 2.66 m, 2H), 2.30 (d, 3H); LCMS: purity: 95%; MS (m/e): 429 (M⁺);430 (MH⁺). 7.4.80 5-Fluoro-N2-[2(R)-{(1R, 2S,5R)-menthyloxycarbonyl}-2,3-dihydrobenzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine(R927062) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine with5-amino-[2(R)-{(1R, 2S, 5R)-menthyloxycarbonyl}]-2,3-dihydrobenzofurangave 5-fluoro-N2-[2(R)-{(1R, 2S,5R)-menthyloxycarbonyl}-2,3-dihydrobenzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine.LCMS: purity: 93%; MS (m/e): 563 (MH⁺). 7.4.81N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2(R)-{(1R, 2S,5R)-menthyloxycarbonyl}-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R927063) In like manner to the preparation ofN4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidineaminewith 5-amino-[2(R)-{(1R, 2S,5R)-menthyloxycarbonyl}-2,3-dihydro]benzofuran gaveN4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2(R)-{(1R, 2S,5R)-menthyloxycarbonyl}-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 93%; MS (m/e): 612 (MH⁺). Formulation of Salts fromBis-SNAr Products 7.4.82N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-Toluenesulfonic Acid Salt (R927070) A dry reaction flask equipped witha magnetic stirring bar, rubber septum and a N₂ inlet was charged withN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(0.220 g, 0.5 mmol) and MeOH (15 mL). To this suspension was addedp-toluenesulfonic acid monohydrate (0.095 g, 0.5 mmol) at 0° C. over aperiod of 2-3 minutes. As soon as the addition of p-toluenesulfonic acidmonohydrate was completed, the suspension turned into a clear solution.It was further stirred for 5 minutes, concentrated using a rotaryevaporator and the residue was recrystallized from EtOH:EtOAc:n-hexanes(1:1:5 mL; v/v) to affordN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt. Alternatively, the residue was taken intoEtOH and precipitated with either n-hexanes or ethyl ether to getN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt as a amorphous solid. ¹H NMR (DMSO-d₆):δ10.60 (s, 1H), 10.07 (bs, 1H), 9.60 (bs, 1H), 8.15 (d, 1H, J=5.1 Hz),7.44 (dd, 2H, J=1.2 and 6.0 Hz), 7.28 (m, 1H), 7.16 (m, 1H), 7.10 (dd,2H, J=1.2 and 6.0 Hz), 6.85 (, d, 1H, J=8.4 Hz), 6.74 (t, 2H, 2.8 Hz),6.19 (t, 1H, J=2.8 Hz), 3.64 (s, 6H), 2.28 (s, 3H), 1.41 (s, 6H); LCMS:purity: 100%; MS (m/e): 440 (MH⁺ for parent base). 7.4.83N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineMethanesulfonic Acid Salt (R927071) In like manner to the preparation ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt, the reaction ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminewith methanesulfonic acid gaveN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminemethanesulfonic acid salt. LCMS: purity: 98%; MS (m/e): 440 (MH⁺; forparent base). 7.4.84N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineBenzenesulfonic Acid Salt (R927072) In like manner to the preparation ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt, the reaction ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminewith benzenesulfonic acid gaveN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminebenzenesulfonic acid salt. ¹H NMR (DMSO-d₆): δ10.61 (s, 1H), 10.00 (bs,1H), 9.57 (bs, 1H), 8.15 (d, 1H, J=4.5 Hz), 7.57 (m, 2H), 7.28 (m, 3H),7.16 (bs, 1H), 6.86 (d, 1H, J=8.4 Hz), 7.76 (bs, 1H), 6.17 (d, 1H, J=2.1Hz), 3.64 (s, 6H), 1.41 (s, 6H); LCMS: purity: 100%; MS (m/e): 440 (MH⁺;for parent base). 7.4.85N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineHydrogen Chloride Salt (R927073) In like manner to the preparation ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt, the reaction ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminewith hydrogen chloride (4M, dioxane) gaveN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminehydrogen chloride salt. LCMS: purity: 100%; MS (m/e): 440 (MH⁺; forparent base). 7.4.86N2-(3,5-Dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineDL-Camphoursulfonic Acid Salt (R927074) In like manner to thepreparation ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt, the reaction ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminewith DL-camphoursulfonic acid gaveN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineDL-camphoursulfonic acid salt. ¹H NMR (DMSO-d₆): δ10.59 (s, 1H), 10.10(bs, 1H), 9.65 (bs, 1H), 8.17 (d, 1H, J=4.5 Hz), 7.27 (m, 1H), 7.15 (bs,1H), 6.86 (d, 1H, J=8.4 H), 6.74 (d, 1H, J=2.1 Hz), 6.19 (m, 1H), 3.64(s, 6H), 2.89 (d, 1H, J=11.7 Hz), 2.66 (m, 1H), 2.48 (m, 2H), 2.40 (d,1H, J=14.7 Hz), 2.23 (dt, 1H, J=3.3 and 18.3 Hz), 1.94 (m, 1H), 1.85 (m,2H), 1.41 (s, 6H), 1.25 (m, 2H), 1.05 (s, 3H), 0.75 (s, 3H); LCMS:purity: 100%; MS (m/e): 440 (MH⁺; for parent base). 7.4.87N2-(3,5-Dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-Tolunesulfonic Acid Salt (R927075) In like manner to the preparationofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt, the reaction ofN2-(3,5-dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminewith p-toluenesulfonic acid gaveN2-(3,5-dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt. ¹H NMR (DMSO-d₆): δ10.65 (s, 1H), 9.95 (bs,1H), 9.40 (bs, 1H), 8.13 (d, 1H, J=4.8 Hz), 7.45 (d, 2H, J=7.8 Hz), 7.26(m, 1H), 7.14 (bs, 1H), 7.09 (d, 2H, J=7.8 Hz), 6.89 (d, 1H, J=8.7 Hz),6.63 (bs, 1H), 2.28 (s, 3H), 2.16 (s, 6H), 1.40 (s, 6H); LCMS: purity:100%; MS (m/e): 408 (MH⁺; for parent base). 7.4.88N2-(3,5-Dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineBenzenesulfonic Acid Salt (R927076) In like manner to the preparation ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt, the reaction ofN2-(3,5-dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminewith benzenesulfonic acid gaveN2-(3,5-dimethylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminebenzenesulfonic acid salt. ¹H NMR (DMSO-d₆): δ10.67 (s, 1H), 10.12 (bs,1H), 9.55 (s, 1H), 8.15 (d, 1H, J=4.8 Hz), 7.57 (m, 2H), 7.28 (m, 4H),7.11 (bs, 3H), 6.90 (d, 1H, J=8.4 Hz), 6.66 (bs, 1H), 1.40 (s, 6H);LCMS: purity: 100%; MS (m/e): 408 (MH⁺; for parent base). 7.4.89N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediaminep-Toluenesulfonic Acid Salt (R927087) In like manner to the preparationofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-4H-benz[1,4-oxazin-3-oxo-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt, the reaction ofN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediaminewith p-toluenesulfonic acid gaveN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediaminep-toluenesulfonic acid salt. LCMS: purity: 100%; MS (m/e): 384 (MH⁺; forparent base). 7.4.90N4-(3,4-Ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminep-Toluenesulfonic Acid Salt (R927090) In like manner to the preparationofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-4H-benz[1,4-oxazin-3-oxo-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt, the reaction ofN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewith p-toluenesulfonic acid gaveN4-(3,4-ethylendioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminep-toluenesulfonic acid salt. ¹H NMR (DMSO-d₆): δ9.99 (bs, 1H), 9.79 (bs,1H), 8.14 (d, 1H, J=4.8 Hz), 7.97 (bd, 1H, J=5.1 Hz), 7.44 (dd, 2H,J=2.4 and 9.0 Hz), 7.25 (m, 1H), 7.14 (m, 5H), 6.80 (d, 1H, J=8.4 Hz),6.64 (m, 1H), 4.36 (s, 2H), 4.22 (s, 4H), 2.64 (d, 3H, J=4.8 Hz), 2.28(s, 3H); LCMS: purity: 100%; MS (m/e): 426 (MH⁺; for parent base).Synthesis of Anilines and mono SNAr Products 7.4.912-Isopropoxy-5-nitropyridine A solution of 2-bromo-5-nitropyridine (1.0g, 4.9 mmol), potassium t-butoxide (6.9 ml, 6.9 mmol, 1N solution inTHF), and isopropyl alcohol (75 mL) was heated at 75° C. for 2 days. Thereaction mixture was concentrated in vacuo and the residue suspended inwater and sonicated at room temperature for several minutes. The productwas collected as a tan solid by filtration. ¹H NMR (CDCl₃): δ9.06 (d,J=3.0 Hz, 1H), 8.31 (dd, J=3.0 and 9.3 Hz, 1H), 6.73 (d, J=9.3 Hz, 1H),5.43 (quintet, J=5.7 Hz, 1H), and 1.37 (d, J=6.3 Hz, 1H). 7.4.925-Amino-2-isopropoxypyridine In like manner to the preparation of ethyl4-aminophenoxyacetate, hydrogenation of 2-isopropoxy-5-nitropyridine wascarried out to prepare 5-amino-2-isopropoxypyridine. ¹H NMR (CDCl₃):δ7.65 (d, J=2.7 Hz, 1H), 7.01 (dd, J=3.0 and 8.7 Hz, 1H), 6.54 (d, J=9.0Hz, 1H), 5.13 (quintet, J=6.6 Hz, 1H), 3.20 (bs, 2H), and 1.32 (d, J=6.6Hz, 6H). 7.4.932-Chloro-5-fluoro-N4-(2-isopropoxypyridin-5-yl)-4-pyrimidineamine In alike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 5-amino-2-isopropoxypyridine werereacted to provide2-chloro-5-fluoro-N4-(2-isopropoxypyridin-5-yl)-4-pyrimidineamine. ¹HNMR (CDCl₃): δ8.30 (d, J=3.0 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 6.81 (bs,1H), 6.75 (d, J=9.0 Hz, 1H), 5.27 (quintet, J=6.6 Hz, 1H), and 1.35 (d,J=6.6 Hz, 6H). 7.4.94 3-Chloro-4-(N-morpholino)nitrobenzene A mixture of2-chloro-4-fluoronitrobenzene (1.36 g, 7.72 mmol) and morpholine (8.0mL, 90 mmol) was heated at 80° C. for 3 hours. The reaction mixture waspoured into water (150 mL) and the product collected as a yellow solidafter filtration. ¹H NMR (CDCl₃): δ8.26 (d, J=3.0 Hz, 1H), 8.11 (dd,J=3.0 ad 9.3 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.91-3.87 (m, 4H), and3.23-3.19 (m, 4H). 7.4.95 3-Chloro-4-(N-morpholino)aniline To a solutionof 3-chloro-4-(N-morpholino)nitrobenzene (1.0 g, 4.1 mmol) inethanol/water (70 mL, 2:1) was added iron powder (1.4 g, 25 mmol)followed by NH₄Cl (0.46 g, 8.6 mmol). The reaction mixture was stirredat room temperature for 10 minutes and then heated at 70° C. for 1.5 h.After cooling to room temperature, the reaction mixture was filteredthrough celite and the filter cake was washed with methanol.Concentration of the filtrate in vacuo gave a white solid, which wasdissolved in ethyl acetate and washed with NaHCO₃ (aq) and brine. Theorganic layer was then dried (MgSO₄), filtered, and concentrated invacuo to give the product as a white solid. ¹H NMR (CDCl₃): δ6.98-6.91(m, H), 6.82 (bs, 1H), 6.67-6.61 (m, 1H), 3.90-3.82 (m, 4H), and3.02-2.90 (m, 4H). 7.4.962-Chloro-N4-[3-chloro-4-(N-morpholino)phenyl]-5-fluoro-4-pyrimidineamineIn a like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-(N-morpholino)anilinewere reacted to provide2-chloro-N4-[3-chloro-4-(N-morpholino)phenyl]-5-fluoro-4-pyrimidineamine.¹H NMR (CDCl₃): δ8.09 (d, J=2.4 Hz, 1H), 7.75 (d, J=3.0 Hz, 1H), 7.55(dd, J=2.7 and 8.7 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 6.92 (bs, 1H),3.99-3.92 (m, 4H), and 3.21-3.14 (m, 4H). 7.4.973-Chloro-4-isopropoxynitrobenzene In a like manner to the preparation of2-isopropoxy-5-nitropyridine, 3-chloro-4-fluoronitrobenzene was reactedwith isopropanol and potassium t-butoxide to provide3-chloro-4-isopropoxynitrobenzene. ¹H NMR (CDCl₃): δ8.26 (d, J=3.0 Hz,1H), 8.11 (dd, J=3.0 and 8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 4.71(quintet, J=6.0 Hz, 1H), and 1.43 (d, J=6.0 Hz, 6H). 7.4.983-Chloro-4-isopropoxyaniline In a like manner to the preparation of3-chloro-4-(N-morpholino)aniline, 3-chloro-4-isopropoxynitrobenzene wasreduced to provide 3-chloro-4-isopropoxyaniline. ¹H NMR (DMSO-d ₆):δ6.80 (d, J=8.7 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 6.43 (dd, J=3.0, 8.7Hz, 1H), 4.92 (bs, 2H), 4.24 (quintet, J=5.7 Hz, 1H), and 1.18 (d, J=5.7Hz, 6H). 7.4.992-Chloro-N4-(3-chloro-4-isopropoxyphenyl)-5-fluoro-4-pyrimidineamine Ina like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-isopropoxyaniline werereacted to provide2-chloro-N4-(3-chloro-4-isopropoxyphenyl)-5-fluoro-4-pyrimidineamine. ¹HNMR (CDCl₃): δ8.04 (d, J=3.0 Hz, 1H), 7.61 (d, J=2.7 Hz, 1H), 7.48 (dd,J=3.0 and 8.7 Hz, 1H), 6.99-6.93 (m, 2H), 4.52 (quintet, J=6.0 Hz, 1H),1.37 (d, J=6.0 Hz, 6H); ¹⁹F NMR (282 MHz, CDCl₃): -158.12; LCMS: purity:94%; MS (m/e): 317 (MH⁺). 7.4.1005-Amino-2-(N,N-dimethylaminomethyl)benzofuran Borane-methyl sulfidecomplex (4.0 mL, 43 mmole) was added to a suspension of2-[(N,N-dimethylamino)carbonyl]-5-nitrobenzofuran (1.0 g, 43 mmole) inanhydrous THF (10 mL). The reaction mixture was heated at reflux for 3h. Upon cooling, the solvent was removed in vacuo to give a gel-likesolid. Cold (0° C.) methanol (50 mL) was cautiously added dropwise andthe resulting mixture was heated at 80° C. for 30 min providing a clearyellow solution. The solvent was removed in vacuo and the resultingsolid was suspended in methanol (50 mL) and HCl (1.5 mL, 4N in dioxane)was added. After heating at 80° C. for 30 min the solvent was removedunder reduced pressure to give an amorphous solid. The solid wasdissolved in methanol (20 mL) and ammonia (2N in methanol) was addeduntil basic. A precipitate formed after dilution with dichloromethane(50 mL). Filtration and concentration gave crude2-(N,N-dimethylaminomethyl)-5-nitrobenzofuran as a yellow oil (1.0g)which was used without further purification. To a suspension of crude2-(N,N-dimethylaminomethyl)-5-nitrobenzofuran (1.0 g) in methanol(degassed, 60 mL) was added Na₂S₂O₄ (0.50 g) and 10% Pd/C (100 mg). Thereaction mixture was stirred under an atmosphere of H₂ for 10 h. Solidswere removed by filtration through Celite® filter aid, and the filtercake was washed several times with methanol. Concentration gave darkyellow oil. The product, 5-amino-2-(N,N-dimethylaminomethyl)benzofuran,was obtained after purification by column chromatography over silica gel(mobile phase: 0% to 5% Methanol (containing 2N NH₃)/dichloromethane).¹H NMR (CD₃OD): δ7.24 (d, 1H, J=8.7 Hz), 6.91 (d, 1H, J=2.4 Hz), 6.76(dd, 1H, J=2.4 and 8.7 Hz), 6.65 (s, 1H), 3.87 (s. 2H), 2.48 (s, 6H).Bis-SNAr and Subsequent Reactions 7.4.101 (±)N2-(2-Carboxyl-2,3-dihydrobenzofuran-5-yl)-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926957) The reaction ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(2-methoxycarbonyl-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinediamineand lithium hydroxide(LiOH) in THF:H₂O at room temperature followed byacidification with 2N HCl aqueous solution gaveN2-(2-carboxyl-2,3-dihydrobenzofuran-5-yl)-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.62 (s, 1H), 9.14 (s, 1H), 8.11 (dd, J=3.6 and 7.5Hz, 2H), 7.81 (dd, J=3.0 and 9.3 Hz, 1H), 7.49-7.44 (m, 2H), 7.22 (dd,J=2.4 and 8.1 Hz, 1H), 6.72 (d, J=9.0 Hz, 1H), 5.21-5.13 (m, 1H), 3.48(dd, J=10.5 and 15.6 Hz, 1H), 3.17 (dd, J=6.0 and 15.6 Hz, 1H); LCMS:purity: 98%; MS (m/e): 486 (MH⁺). 7.4.102 (±)N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-2,3-dihydroxypropylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine(R926958) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,racemicN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(2-methoxycarbonyl-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinediamineand racemic 2,3-dihydroxypropyl amine were reacted to provide a mixtureof two racemates ofN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-2,3-dihydroxypropylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.06 (d, J=2.4 Hz, 1H), 7.92 (dd, J=2.4 and 4.2 Hz,1H), 7.68 (dd, J=3.0 and 9.3 Hz, 1H), 7.41-7.37 (m, 1H), 7.34-7.29 (m,1H), 7.26-7.19 (m, 1H), 6.82 (d, J=8.7 Hz, 1H), 5.18-5.11 (m, 1H),3.74-3.66 (m, 1H), 3.60-3.52 (m, 1H), 3.50-3.42 (m, 2H), 3.38-3.35 (m,1H), 3.21 (dd, J=7.2 and 13.5 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD):-169.15, -60.23; LCMS: purity: 98%; MS (m/e): 559 (MH⁺). 7.4.103 (±)N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine(R926959) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,racemicN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(2-methoxycarbonyl-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinediamineand ethanolamine were reacted to provide (±)N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.65-8.05 (m, 1H), 7.94-7.90 (m, 1H), 7.68 (dd, J=3.0and 9.3 Hz, 1H), 7.39-7.35 (m, 1H), 7.31 (dd, J=1.2 and 8.7 Hz, 1H),6.82 (d, J=8.1 Hz, 1H), 5.18-5.10 (m, 1H), 3.64-3.21 (m, 7H); ¹⁹F NMR(282 MHz, CD₃OD): -169.19, -60.24; LCMS: purity: 98%; MS (m/e): 529(MH⁺). 7.4.104 (±)N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethyl-N-methylamino]carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine(R926960) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,racemicN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(2-methoxycarbonyl-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinediamineand N-methylethanolamine were reacted to provide (±)N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethyl-N-methylamino]carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine.LCMS: purity: 95%; MS (m/e): 543 (MH⁺). 7.4.105N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-isopropylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine(R926961) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,racemicN4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(2-methoxycarbonyl-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinediamineand isopropyl amine were reacted to provide (±)N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2-(N-isopropylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine.LCMS: purity: 94%; MS (m/e): 526 (MH⁺). 7.4.1065-Fluoro-N4-(2-isopropoxypyridin-5-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926962) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-5-fluoro-N4-(2-isopropoxypyridin-5-yl)-4-pyrimidineamine with3-(N-methylamino)carbonylmethyleneoxyaniline in isopropanol gave5-fluoro-N4-(2-isopropoxypyridin-5-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.34 (s, 1H), 9.22 (s, 1H), 8.60-8.56 (m, 1H), 8.07(d, 3.6 Hz, 1H), 8.02-7.92 (m, 2H), 7.36 (bs, 1H), 7.25 (d, J=8.4 Hz,1H), 7.08 (t, J=8.1 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.46 (dd, J=2.1 and8.1 Hz, 1H), 5.17 (quintet, J=6.3 Hz, 1H), 4.34 (s, 2H), 2.63 (d, J=3.9Hz, 3H), 1.27 (d, J=6.6 Hz, 6H); LCMS: purity: 93%; MS (m/e): 427 (MH⁺).7.4.107N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926963) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand ethanolamine were reacted to provideN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.90 (d, J=3.3 Hz, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.54(dd, J=2.1 and 8.7 Hz, 1H), 7.34-7.29 (m, 1H), 7.17-7.14 (m , 2H), 7.03(d, J=8.7 Hz, 1H), 6.62-6.56 (m, 1H), 4.39 (s, 2H), 3.87 (s, 3H), 3.62(t, J=5.7 Hz, 2H), 3.40 (t, J=5.7 Hz, 2H); ¹⁹F NMR (282 MHz, CD₃OD):-168.65; LCMS: purity: 97%; MS (m/e): 462 (MH⁺). 7.4.108 (±)N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926964) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand racemic 2,3-dihydroxypropyl amine were reacted to provide (±)N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.35 (s, 1H), 9.23 (s, 1H), 8.09 (d, J=4.2Hz, 1H),7.87-7.78 (m, 2H), 7.70 (dd, J=2.4 and 9.0 Hz, 1H), 7.32-7.27 (m, 2H),7.15-7.08 (m, 2H), 6.48 (dd, J=2.4 and 9.0 Hz, 1H), 4.38 (s, 2H), 3.82(s, 3H), 3.55-3.21 (m, 5H), 3.08-2.98 (m, 2H); LCMS: purity: 98%; MS(m/e): 493(MH⁺). 7.4.109N2,N4-Bis(4-benzyloxy-3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926965) In a like manner to the preparation ofN2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-benzyloxyaniline werereacted to provideN2,N4-bis(4-benzyloxy-3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d ₆): δ9.43 (s, 1H), 9.27 (s, 1H), 8.09 (d, J=4.2 Hz, 1H),7.76 (dd, J=2.1 and 5.4 Hz, 2H), 7.62 (dd, J=2.4 and 9.6 Hz, 1H),7.48-7.29 (m, 11H), 7.17 (d, J=8.7 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 5.18(s, 2H), 5.12 (s, 2H); LCMS: purity: 97%; MS (m/e): 562 (MH⁺). 7.4.110N4-(4-Benzyloxy-3-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926966) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction ofN4-(4-benzyloxy-3-chlorophenyl)-2-chloro-5-fluoro-4-pyrimidineamine with3-[(N-methylamino)carbonylmethyleneoxy]aniline gaveN4-(4-benzyloxy-3-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.64 (s, 1H), 9.53 (s, 1H), 8.13 (d, J=4.2 Hz, 1H),7.99-7.94 (m, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.67 (dd, J=2.7 and 8.7 Hz,1H), 7.48-7.07 (m, 9H), 6.52 (dd, J=1.8 and 8.1 Hz, 1H), 5.18 (s, 2H),4.35 (s, 2H), 2.62 (d, J=4.8 Hz, 3H); LCMS: purity: 98%; MS (m/e):509(MH⁺). 7.4.111N4-(3-Chloro-4-methoxyphenyl)-N2-[3-(N-cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R926967) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand cyclopropylamine were reacted to provideN4-(3-chloro-4-methoxyphenyl)-N2-[3-(N-cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.88 (s, 1H), 9.70 (s, 1H), 8.17 (d, J=4.8 Hz, 1H),8.06 (d, J=3.9 Hz, 1H), 7.79-7.76 (m, 1H), 7.65 (dd, J=2.4 and 8.1 Hz,1H), 7.22-7.11 (m, 4H), 6.57-6.52 (m, 1H), 4.32 (s, 2H), 3.82 (s, 3H),2.69-2.61 (m, 1H), 0.63-0.56 (m, 2H), 0.47-0.43 (m, 2H); LCMS: purity:92%; MS (m/e): 459 (MH⁺). 7.4.112N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926968) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with3-chloro-4-hydroxy-5-methylaniline gaveN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.49 (s, 1H), 9.17 (s, 1H), 8.66 (m, 1H), 8.07 (d,J=4.2 Hz, 1H), 7.71-7.62 (m, 2H), 7.46 (bs, 1H), 7.18 (bs, 1H), 7.09 (d,J=9.0, 1H), 3.82 (s, 3H), 2.09 (s, 3H); LCMS: purity: 95%; MS (m/e): 410(MH⁺). 7.4.113N4-(3-Chloro-4-methoxyphenyl)-N2-[3-(N-cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R926969) In a like manner to the preparation ofN4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineand cyclobutylamine were reacted to provideN4-(3-chloro-4-methoxyphenyl)-N2-[3-(N-cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.52 (s, 1H), 9.37 (s, 1H), 8.21 (d, J=7.8 Hz, 1H),8.11 (d, J=3.3 Hz, 1H), 7.79 (d, J=3.3 Hz, 1H), 7.69 (dd, J=2.4 and 9.6Hz, 1H), 7.27-7.22 (m, 2H), 7.16-7.08 (m, 2H), 6.50 (dd, J=2.4 and 8.1Hz, 1H), 4.32 (s, 2H), 4.24 (q, 8.1 Hz, 1H), 3.82 (s, 3H), 2.18-2.05 (m,2H), 2.00-1.89 (m, 2H), 1.64-1.53 (m, 2H); LCMS: purity: 95%; MS (m/e):473(MH⁺). 7.4.114N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926970) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3,5-dimethoxyaniline gaveN4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ11.92 (s, 1H), 9.55 (s, 1H), 9.09 (s, 1H), 8.12 (d,J=6.0 Hz, 1H), 7.52-7.46 (m, 2H), 7.22 (d, J=8.7 Hz, 1H), 6.91 (d, J=2.4Hz, 1H), 6.05 (t, J=2.4 Hz, 1H), 3.61 (s, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆): -164.56, -76.64; LCMS: purity: 98%; MS (m/e): 448 (MH⁺). 7.4.115N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R926971) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3-chloro-4-hydroxy-5-methylaniline gaveN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ11.95 (s, 1H), 9.50 (s, 1H), 9.00 (s, 1H), 8.56 (s,1H), 8.09 (d, J=3.6 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.49-7.40 (m, 2H),7.24 (s, 1H), 7.22-7.19 (m, 1H), 2.07 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆): --165.46, -76.51; LCMS: purity: 94%; MS (m/e): 453 (MH⁺). 7.4.116N4-(3-Chloro-4-methoxyphenyl)-N2-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926972) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with3-chloro-4-methoxy-5-methylaniline gaveN4-(3-chloro-4-methoxyphenyl)-N2-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.38 (s, 1H), 9.25 (s, 1H), 8.09 (d, J=3.6 Hz, 1H),7.70 (d, J=2.4, 1H), 7.66-7.58 (m, 2H), 7.33 (d, J=2.4 Hz, 1H), 7.11 (d,J=8.7 Hz, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 2.14 (s, 3H); LCMS: purity:94%; MS (m/e): 424 (MH⁺). 7.4.117N4-(3-Chloro-4-isopropoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R926973) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-isopropoxyphenyl)-5-fluoro-4-pyrimidineamine.with 3-(N-methylamino)carbonylmethyleneoxyaniline gaveN4-(3-chloro-4-isopropoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.30 (s, 1H), 9.21 (s, 1H), 8.08 (d, J=3.6 Hz, 1H),7.95-7.88 (m, 1H), 7.81-7.79 (m, 1H), 7.69 (dd, J=3.0 and 8.7 Hz, 1H),7.32-7.28 (m, 2H), 7.13-7.07 (m, 2H), 6.49-6.44 (m, 1H), 4.57 (quintet,J=6.0 Hz, 1H), 4.34 (s, 2H), 2.63 (d, J=4.8 Hz, 3H), 1.26 (d, J=6.0 Hz,6H); LCMS: purity: 99%; MS (m/e): 461 (MH⁺). 7.4.118N4-(3-Chloro-4-methoxy-5-methylphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine(R926974) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-4-pyrimidineaminewith 3-(N-methylamino)carbonylmethyleneoxyaniline gaveN4-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ8.01 (d, J=5.4 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H),7.40-7.29 (m, 2H), 7.10-7.04 (m, 2H), 6.89-6.84 (m, 1H), 4.38 (s, 2H),3.79 (s, 3H), 2.79 (s, 3H), 2.25 (s, 3H); LCMS: purity: 96%; MS (m/e):447(MH⁺). 7.4.119N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine(R926975) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine with6-aminoindole gaveN4-(3,4-dichlorophenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ7.99 (d, J=2.4, 1H), 7.91 (d, J=3.6 Hz, 1H), 7.72 (dd,J=3.0 and 8.7 Hz, 1H), 7.60 (d, J=1.2 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H),7.25 (d, J=9.0 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.06 (dd, J=1.8 Hz, 1H),6.40 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz, CD₃OD): -169.48; LCMS: purity:96%; MS (m/e): 390 (MH⁺). 7.4.120 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine (R926976) In a likemanner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with6-aminoindole gave N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d ₆):δ10.82 (s, 1H), 9.22 (s, 1H), 9.02 (s, 1H), 8.05 (d, J=3.6 Hz, 1H), 7.85(d, J=2.4 Hz, 1H), 7.81-7.76 (m, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.21 (d,J=1.8 Hz, 1H), 7.19-7.15 (m, 1H), 7.03 (d, J=8.7 Hz, 1H), 6.30 (bs, 1H),3.81 (s, 3H); LCMS: purity: 93%; MS (m/e): 384(MH⁺). 7.4.121N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine(R926977) In a like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 6-aminoindole gaveN4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ11.91 (s, 1H), 10.83 (s, 1H), 9.48 (s, 1H), 8.91 (s,1H), 8.09 (d, J=3.6 Hz, 1H), 7.84 (bs, 1H), 7.68 (dd, J=3.0 and 9.3 Hz,1H), 7.54-7.51 (m, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.20 (s, 1H), 7.18-7.14(m, 2H), 6.32-6.28 (m, 1H); LCMS: purity: 98%; MS (m/e): 427 (MH⁺).7.4.122N4-(3-Chloro-4-methoxyphenyl)-N2-[2-(N,N-dimethylaminomethyl)benzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R926978) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-2-(N,N-dimethylaminomethyl)benzofuran were reacted to provideN4-(3-chloro-4-methoxyphenyl)-N2-[2-(N,N-dimethylaminomethyl)benzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.27 (s, 1H), 9.15 (s, 1H), 8.06 (d, J=3.6 Hz, 1H),7.85 (s, 1H), 7.79 (d, J=3.0 Hz, 1H), 7.69-7.63 (m, 1H), 7.35 (bs, 1H),7.07 (d, J=8.7 Hz, 1H), 6.59 (s, 1H), 3.83 (s, 3H), 3.56 (s, 2H), 2.21(s, 6H); LCMS: purity: 97%; MS (m/e): 443 (MH⁺). 7.4.123N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(N,N-dimethylaminomethyl)benzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R926979) In like manner to the preparation5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 5-amino-2-(N,N-dimethylaminomethyl)benzofuran were reacted toprovideN4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(N,N-dimethylaminomethyl)benzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 99%; MS (m/e): 483 (MH⁻). 7.4.124N4-(3,4-Dichlorophenyl)-N2-[2-(N,N-dimethylaminomethyl)benzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R926980) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and5-amino-2-(N,N-dimethylaminomethyl)benzofuran were reacted to provideN4-(3,4-dichlorophenyl)-N2-[2-(N,N-dimethylaminomethyl)benzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ7.99 (bs, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.72 (d, J=2.4Hz, 1H), 7.43 (d, J=8.7 Hz,, 1H), 7.40-7.33 (m, 2H), 7.26 (dd, J=1.8 and8.7 Hz, 1H), 6.97 (s, 1H), 6.75 (d, J=2,4 Hz, 1H), 6.58 (s, 1H), 3.67(s, 2H), 2.38 (s, 6H); ¹⁹F NMR (282 MHz, CDCl₃): -47438; LCMS: purity:94%; MS (m/e): 445 (M-1). 7.4.125N2-(3-Chloro-4-methoxyphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R926981) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-5-fluoro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 3-chloro-4-methoxyaniline were reacted to provideN2-(3-chloro-4-methoxyphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ12.07 (s, 1H), 10.09 (s, 1H), 9.75 (s, 1H), 8.20 (d,J=4.2 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.52 (bs, 1H), 7.44-7.34 (m, 2H),7.27 (d, J=8.7 Hz, 1H), 7.03 (d, J=9.3 Hz, 1H), 3.77 (s, 3H); LCMS:purity: 96%; MS (m/e): 453 (MH⁺). 7.4.126N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine(R926982) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-aminoindole were reacted to provideN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ10.81 (s, 1H), 10.54 (s, 1H), 9.24 (s, 1H), 8.81 (s,1H), 8.03 (d, J=3.3 Hz, 1H), 7.81 (bs, 1H), 7.45-7.38 (m, 1H), 7.34-7.31(m, 2H), 7.21-7.14 (m, 2H), 6.83 (d, J=9.0 Hz, 1H), 6.28 (d, J=2.4 Hz,1H), 1.38 (s, 3H); LCMS: purity: 98%; MS (m/e): 419 (MH⁺). 7.4.127N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine(R926983) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 5-amino-2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran werereacted to provideN4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ12.09 (s, 1H), 10.15 (s, 1H), 9.59 (s, 1H), 8.15 (d,J=3.9 Hz, 1H), 7.52-7.39 (m, 3H), 7.26 (d, J=8.7 Hz, 1H), 7.13 (d, J=8.4Hz, 1H), 6.69 (d, J=8.7 Hz, 1H), 5.64-5.57 (m, 1H), 3.43-3.27 (m, 2H),3.06 (s, 3H), 2.85 (s, 3H); LCMS: purity: 96%; MS (m/e): 501(MH⁺).7.4.128N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926984) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-methoxy-5-trifluoromethylaniline were reacted to provideN4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ11.92 (s, 1H), 9.61 (s, 1H), 9.50 (s, 1H), 8.18 (d,J=3.6 Hz, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.48-7.41 (m, 2H), 7.22 (d,J=8.7 Hz, 1H), 6.71 (bs, 1H), 3.70 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d ₆):-163.55, -76.50, -61.83; LCMS: purity: 98%; MS (m/e): 486 (MH⁺). 7.4.129N2-(3,5-Dichlorophenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R926985) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3,5-dichloroaniline were reacted to provideN2-(3,5-dichlorophenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ11.95 (bs, 1H), 9.65 (d, J=3.3 Hz, 2H), 8.19 (d,J=3.9 Hz, 1H), 7.71 (d, J=1.8 Hz, 2H), 7.41-7.35 (m, 2H), 7.27 (d, J=9.3Hz, 1H), 6.99 (t, J=1.8 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d ₆): -163.24,-76.23; LCMS: purity: 92%; MS (m/e): 457 (MH⁺). 7.4.130N4-[3-Chloro-4-(N-morpholino)phenyl]-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926986) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-[3-chloro-4-(N-morpholino)phenyl]-5-fluoro-4-pyrimidineamineand 3,5-dimethoxyaniline were reacted to provideN4-[3-chloro-4-(N-morpholino)phenyl]-5-fluoro-N2-(3,5-dimethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.80 (bs, 1H), 9.53 (bs, 1H), 8.16 (d, J=4.2 Hz,1H), 7.78-7.71 (m, 2H), 7.10 (d, J=8.7 Hz, 1H), 6.81 (bs, 2H),6.16-6.11(m, 1H), 3.75-3.71 (m, 4H), 3.63 (s, 6H), 2.96-2.91 (m, 4H); LCMS:purity: 95%; MS (m/e): 460 (MH⁺). 7.4.131N4-[3-Chloro-4-(N-morpholino)phenyl]-5-fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926987) In like manner to the preparation of5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine,2-chloro-N4-[3-chloro-4-(N-morpholino)phenyl]-5-fluoro-4-pyrimidineamineand 3-methoxy-5-trifluoromethylaniline were reacted to provideN4-[3-chloro-4-(N-morpholino)phenyl]-5-fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.53 (s, 1H), 9.45 (s, 1H), 8.16 (d, J=3.6 Hz, 1H),7.77-7.73 (m, 2H), 7.64-7.57 (m, 2H), 7.10 (d, J=8.7 Hz, 1H), 6.72 (bs,1H), 3.76-3.70 (m, 7H), 2.95-2.91 (m, 4H); ¹⁹F NMR (282 MHz, DMSO-d ₆):-163.57, -61.62; LCMS: purity: 99%; MS (m/e): 498 (MH⁺). 7.4.132N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminep-Toluenesulfonic Acid Salt (R926989) In a like manner to thepreparation ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-4H-benz[1,4-oxazin-3-oxo-6-yl)-5-fluoro-2,4-pyrimidinediaminep-toluenesulfonic acid salt,N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminewas reacted with p-toluenesulfonic acid monohydrate to provideN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminep-toluenesulfonic acid salt. ¹H NMR (DMSO-d ₆): δ9.91 (bs, 1H), 9.65(bs, 1H), 8.16 (d, J=4.5 Hz, 1H), 8.02-7.94 (m, 1H), 7.78 (d, J=2.7 Hz,1H), 7.64 (dd, J=2.7 and 9.0 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.22-7.06(m, 6H), 6.63-6.56 (,m, 1H), 4.34 (s, 2H), 3.83 (s, 3H), 2.63 (d, J=4.5Hz, 3H), 2.28 (s, 3H). 7.4.133N4-(3-Chloro-4-methoxyphenyl)-N2-(3,5-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R926990) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with3,5-dichloroaniline gaveN4-(3-chloro-4-methoxyphenyl)-N2-(3,5-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.68 (s, 1H), 9.53 (s, 1H), 8.16 (d, J=3.9 Hz, 1H),7.69 (d, J=1.8 Hz, 2H), 7.66-7.58 (m, 2H), 7.13 (d, J=9.3 Hz, 1H), 7.01(t, J=2.1 Hz, 1H), 3.83 (s, 3H); LCMS: purity: 97%; MS (m/e): 415 (MH⁺).7.4.134N4-(3-Chloro-4-methoxyphenyl)-N2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine(R926991) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with3,5-dimethylaniline gaveN4-(3-chloro-4-methoxyphenyl)-N2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ10.10 (bs, 1H), 9.79 (bs, 1H), 8.21 (d, J=4.8 Hz,1H), 7.71 (d, J=2.4 Hz, 1H), 7.59 (dd, J=2.4 and 9.0 Hz, 1H), 7.14 (d,J=9.0 Hz, 1H), 7.09 (bs, 2H), 6.65 (s, 1H), 3.85 (s, 3H), 2.16 (s, 6H);LCMS: purity: 99%; MS (m/e): 374 (MH⁺). 7.4.135N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine(R926992) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with3-methoxy-5-trifluoromethylaniline gaveN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.52 (s, 1H), 9.40 (s, 1H), 8.14 (d, J=3.9 Hz, 1H),7.72 (d, J=2.4 Hz, 1H), 7.68 (dd, J=2.7 and 9.0 Hz, 1H), 7.64-7.60 (m,1H), 7.59-7.55 (m, 1H), 3.84 (s, 3H), 3.72 (s, 3H); LCMS: purity: 95%;MS (m/e): 444 (MH⁺). 7.4.136N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(3,4,5-trimethylphenyl)-2,4-pyrimidinediamine(R926993) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine with3,4,5-trimethylaniline gaveN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3,4,5-trimethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ9.23 (bs, 1H), 8.91 (bs, 1H), 8.04 (d, J=3.6 Hz,1H), 7.78-7.66 (m, 2H), 7.22 (s, 2H), 7.07 (d, J=8.7 Hz, 1H), 3.83 (s,3H), 2.12 (s, 6H), 2.03 (s, 3H); LCMS: purity: 98%; MS (m/e): 388 (MH⁺).7.4.137N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethylphenyl)-2,4-pyrimidinediamine(R926994) In a like manner to the preparation ofN4-(4-chloro-3-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,the reaction of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewith 3,4,5-trimethylaniline gaveN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethylphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ10.57 (s, 1H), 9.24 (s, 1H), 8.78 (s, 1H), 8.02 (d,J=3.9 Hz, 1H), 7.31 (dd, J=2.1 and 8.4 Hz, 1H), 7.26-7.22 (m, 3H), 6.86(d, J=8.7 Hz, 1 H), 2.11 (s, 6H), 2.02 (s, 3H), 1.40 (s, 6H); LCMS:purity: 99%; MS (m/e): 422 (MH⁺). 7.4.1385-Fluoro-N4-[1-(N-methylaminocarbonyl)indol-6-yl]-N2-(3,5-dimethoxyphenyl)-2,4-pyrimidinediamine(R926995) To a suspension of5-fluoro-N4-[(1H)-indol-6-yl]-N2-(3,5-dimethoxyphenyl)-2,4-pyrimidinediamine(0.045mg, 0.12 mmol), in THF (0.75 mL) at 0° C. were added triethylamine(0.025 mL, 0.12 mmol), 4-N,N-dimethylaminopyridine (0.5 mg) followed bydiphosgene (8.5 μL, 0.071 mmol). The resulting reaction mixture was thenstirred at room temperature for 1 hour, quenched with an aqueoussolution of methylamine (40%, 1.5 mL), stirred for 5 minutes and dilutedwith water. The aqueous solution was extracted with ethyl acetate,solvent was evaporated and the residue was chromatographed (silica gel;CH₂Cl₂ then 2-5% of 2M NH₃/MeOH in CH₂Cl₂) to yield5-fluoro-N4-[1-(N-methylaminocarbonyl)indol-6-yl]-N2-(3,5-dimethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d ₆): δ10.90 (bs, 1H), 9.62 (bs, 1H), 9.49-9.42 (m, 1H),8.08 (d, J=3.3 Hz, 1H), 7.40 (bs, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.30 (t,J=2.7 Hz, 1H), 7.09 (dd, J=1.5 and 8.7 Hz, 1H), 6.49 (t, J=2.4 Hz, 1H),6.41-6.36 (m, 1H), 6.29 (d, J=2.4 Hz, 1H), 3.69 (s, 6H), 2.47 (d, J=4.2Hz, 3H); LCMS: purity: 94%; MS (m/e): 437 (MH⁺). Snthesis of Anilines7.4.139 2-Chloro-6-methyl-4-nitrophenol To a suspenssion of commerciallyavailable 6-methyl-4-nitrophenol (5 g, 32.6 mmol) in water (300 mL) atroom temperature was added N-chlorosuccinimide (8.7 g, 32.6 mmol)followed by an aqueous solution of potassium hydroxyde 5N (13 mL, 65.2mmol). After stirred at room temperature for 2 hours, the resultingreaction was acidified with 2N HCl (pH >2) and extracted with ethylacetate (3 × 200 mL). The organic phase was separated, washed withbrine, dried (Na₂SO₄), concentrated and the resulting residue waspurified by flash chromatography (EtOAc:n-hexanes 15 : 85; v/v) toafford 2-chloro-6-methyl-4-nitrophenol (3.7 g, 60%). ¹H NMR (DMSO-d₆):δ10.84 (1H, s), 8.20 (1H, d, J=3.3 Hz), 8.13 (1H, dt, J=2.7 Hz, J=0.6Hz), 2.39 (3H, s); LCMS: purity: 96.69%. 7.4.1404-Amino-2-chloro-6-methylphenol 2-Chloro-6-methyl-4-nitrophenol (2.5 g,13.32 mmol) was dissolved in glacial AcOH (22 mL), and iron powder (2.23g, 40 mmol) was added. The mixture was heated at 90° C. with mechanicalstirring for 2 hours, then was cooled to room temperature and dilutedwith EtOAc (200 mL). The mixture was filtered through a pad of Celite.The filtrate was washed with brine, dried (Na₂SO₄) and concentrated invacuo. The resulting residue was purified by chromatography on silicagel with CH₂Cl₂ to give 4-amino-2-chloro-6-methylphenol (1.03 g, 50%).¹H NMR (DMSO-d₆): δ8.02 (1H, d, J=0.9 Hz), 6.47 (1H, d, J=2.1 Hz), 6.38(1H, d, J=2.4 Hz), 4.74 (2H, s), 2.16 (3H, s). 7.4.1413-Chloro-4-methoxy-5-methylnitrobenzene To a solution of2-chloro-6-methyl-4-nitrophenol (1.2 g, 6.5 mmol) in acetone (10 mL),was added potassium carbonate (1.34 g, 9.75 mmol) followed by dimethylsulfate (1.33 mL, 7.8 mmol). The mixture was stirred under reflux for 2hours. Ammonium hydroxyde (1 mL) was added and the mixture was heatedunder reflux for 30 minutes. The mixture was cooled to room temperatureand the solvent was removed in vacuo. The residue was poured into water,saturated with sodium chloride and the resulting solid was filtered togive the desired 3-chloro-4-methoxy-5-methylnitrobenzene (1.1 g, 84%).¹H NMR (DMSO-d₆): δ8.28 (1H, d, J=2.7 Hz), 8.24 (1H, dt, J=2.7 Hz,J=0.75 Hz), 3.95 (3H, d, J=0.9 Hz), 2.48 (3H, d, J=0.9 Hz); LCMS:purity: 98%. 7.4.142 3-Chloro-4-methoxy-5-methylaniline3-Chloro-4-methoxy-5-methylnitrobenzene (1.1 g, 5.4 mmol) was dissolvedin glacial AcOH (9 mL), and iron powder (0.917 g, 16.4 mmol) was added.The mixture was heated at 90° C. under a mechanical stirring for 2hours, then was cooled to room temperature and diluted with EtOAc (200mL). The mixture was filtered through a pad of Celite. The filtrate waswashed with brine, dried (Na₂SO₄) and concentrated in vacuo. The residuewas purified by chromatography on silica gel with CH₂Cl₂ to give3-chloro-4-methoxy-5-methylaniline. ¹H NMR (DMSO-d₆): δ6.51 (1H, d,J=2.7 Hz), 6.41 (1H, dd, J=1.8 Hz, J=0.9 Hz), 5.11 (2H, s), 3.68 (3H, d,J=0.9 Hz), 2.21 (3H, s); LCMS: purity: 95%. 7.4.143 (±)2-Ethoxycarbonyl-2-methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine A mixture ofpotassium fluoride (KF) (1.8 g, 32.4 mmol), DMF (10 mL),diethyl-2-bromo-2-methylmalonate (3.2 g, 12.9 mmol), and4-nitro-2-aminophenol (2 g, 12.9 mmol) was stirred for 16 hours, thenpoured into water, and extracted with EtOAc. The extract was washed withbrine, dried, and concentrated to give the desired (±)2-ethoxycarbonyl-2-methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine , which wasrecrystallized from EtOH (2.2 g, 62%). ¹H NMR (DMSO-d₆): δ11.47 (1H, s),7.99 (1H, dd, J=9 Hz, J=2.7 Hz), 7.85 (1H, d, J=2.7 Hz), 7.36 (1H, d,J=8.7 Hz), 4.23 (2H, q, J=7 Hz), 1.85 (3H, s), 1.17 (3H, t, J=7.2 Hz);LCMS: purity: 98 %; MS (m/e): 281 (MH⁺). 7.4.144 (±)6-Amino-2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz[1,4]oxazine A solutionof (±) 2-ethoxycarbonyl-2-methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine (0.5g, 1.78 mmol) in methanol was hydrogenated at 30 PSI for 1 hour in thepresence of 10% Pd/C (0.05 g, 10% by weight). After the filtrationthrough a Celite pad, the solvent was removed under reduced pressure toobtain (±) 6-amino-2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz[1,4]oxazine.¹H NMR (DMSO-d₆): δ10.73 (1H, s), 6.76 (1H, d, J=12 Hz), 6.23-6.20 (2H,m), 5.0 (2H, s), 4.16 (2H, q, J=6.9 Hz), 1.69 (3H, s), 1.15 (3H, t,J=6.9 Hz); LCMS: purity: 99 %; MS (m/e): 251 (MH⁺). 7.4.1453,5-Dimethy-4-methoxynitrobenzene To a solution of2,6-dimethyl-4-nitrophenol (1 g, 5.9 mmol) in acetone (9 mL), was addedpotassium carbonate (1.22 g, 8.85 mmol) followed by dimethyl sulfate(0.68 mL, 7.1 mmol). The mixture was stirred under reflux for 2 hours.Ammonium hydroxyde (1 mL) was added and the mixture was heated underreflux for an extra 30 minutes. The mixture was cooled to roomtemperature and the solvent was removed in vacuo. The residue was pouredinto water, saturated with sodium chloride and the resulting solid wasfiltered to give the desired 3,5-dimethyl-4-methoxynitrobenzene. ¹H NMR(DMSO-d₆): δ8.06 (2H, s), 3.84 (3H, s), 2.42 (6H, s); LCMS: purity: 91%.7.4.146 3,5-Dimethyl-4-methoxyaniline A solution of3,5-dimethyl-4-methoxynitrobenzene (0.83 g, 4.5 mmol) in methanol washydrogenated at 30 PSI for 1 hour in the presence of 10% Pd/C (0.1 g,10% by weight). After the filtration through a Celite pad, the solventwas removed under reduced pressure to obtain3,5-dimethyl-4-methoxyaniline. ¹H NMR (DMSO-d₆): δ6.28 (2H, s), 4.69(2H, brads), 3.60 (3H, d, J=0.9 Hz), 2.16 (6H, s); LCMS: purity: 100 %.7.4.147N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940358 To a solution of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine(0.1 g, 0.3 mmol) in (2 mL) was added 4-amino-2-chloro-6-methylphenol(0.146 g, 0.9 mmol). The mixture was heated in a sealed tube at 100° C.for 24 hours. The resulting reaction was diluted with H₂O (10 mL),acidified with 2N HCl (pH >2), saturated with sodium chloride and theresulting solid was filtered to give the desiredN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.Purification can be done by filtration through a pad of silica gel using1-5% MeOH in CH₂Cl₂ or by crystallization using an appropriate solventsystem. Alternatively, the reaction of equimolar amount of2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-3-6-yl)-5-fluoro-4-pyrimidineaminewith 4-amino-2-chloro-6-methylphenol in MeOH in a pressure tube at 110°C. for 24 hours or, in EtOH using microwave at 175° C. for 30-60 minfollowed by aqueous work up, also gaveN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.78 (1H, s), 10.00 (1H, s), 9.58 (1H, s), 8.91 (1H,s), 8.23 (1H, d, J=4.8 Hz), 7.57 (1H, s), 7.37 (1H, dd, J=8.7 Hz, J=2.1Hz), 7.27 (2H, m), 6.98 (1H, d, J=8.7 Hz), 2.22 (3H, s), 1.50 (6H, s);LCMS: purity: 98 %; MS (m/e): 444 (MH⁺). 7.4.148N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940361 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-chloro-4-methoxy-5-methylaniline were reacted to yieldN2-(3-chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.72 (1H, s), 9.55 (1H, s), 9.35 (1H, s), 8.20 (1H,d, J=4.2 Hz), 7.75 (1H, d, J=2.4 Hz), 7.46 (1H, d, J=2.1 Hz), 7.36 (1H,m), 7.28 (1H, m), 7.00 (1H, d, J=8.7 Hz), 3.76 (3H, s), 2.25 (3H, s),1.50 (6H, s); LCMS: purity: 98.99 %; MS (m/e): 458 (MH⁺). 7.4.149N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamineR940363 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-aminoindazole were reacted to yieldN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.71 (1H, s), 9.64 (1H, s), 9.42 (1H, s), 8.24 (1H,d, J=3.9 Hz), 8.09 (1H, s), 8.01 (1H, s), 7.66 (1H, d, J=9 Hz), 7.52(1H, d, J=8.7 Hz), 7.37 (2H, m), 7.00 (1H, d, J=8.7 Hz), 1.50 (6H, s);LCMS: purity: 96.09 %; MS (m/e): 420 (MH⁺). 7.4.150N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamineR940364 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]-oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]-oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-aminoindazole were reacted to yieldN4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.07 (1H, s), 9.73 (1H, s), 9.40 (1H, s), 8.29 (1H,d, J=3.6 Hz), 8.12 (1H, s), 8.00 (1H, s), 7.78 (1H, dd, J=8.7 Hz, J=2.4Hz), 7.60 (1H, s), 7.36 (2H, m); LCMS: purity: 94.39 %; MS (m/e): 428(MH⁺). 7.4.151 (±)2-Chloro-N4-(2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineThe reaction flask equipped with a magnetic stirring bar and a rubberseptum and N₂ inlet was charged with (±)6-amino-2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz[1,4]oxazine (0.45 g, 1.8mmol), MeOH (4mL), H₂O (2 mL) and 2,4-dichloro-5-fluoropyrimidine (0.36g, 2.2 mmol). The reaction mixture was stirred at 60° C. for 1 hour,diluted with H₂O (50 mL), acidified with 2N HCl (6 mL) and sonicated.The solid obtained was filtered, washed with H₂O and dried. The crudewas recrystallized from EtOAc:n-hexanes to produce (±)2-chloro-N4-(2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ11.21 (1H, s), 10.05 (1H, s), 8.39 (1H, d, J=3.6 Hz),7.41-7.34 (2H, m), 7.13 (1H, d, J=9Hz), 4.20 (2H, q, J=7.2 Hz), 1.78(3H, s), 1.17 (3H, t, J=7.2 Hz); LCMS: purity: 95 %; MS (m/e): 381(MH⁺). 7.4.152 (±)N4-(2-Ethoxycarbonyl-2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineIn like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-(methoxycarbonylmethyleneoxy)aniline were reacted to yield (±)N4-(2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine.7.4.1535-Fluoro-N4-[2-methyl-2-(N-methylaminocarbonyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineR940365 A mixture ofN4-(2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(0.069 g, 1.3 mmol), methylamine hydrochloride salt (0.088 g, 1.3 mmol)and diisopropylethylamine (230 μL, 1.3 mmol) in MeOH (2 mL) was stirredin a pressure vial at 90° C. for 4 hours. The reaction was cooled toroom temperature, diluted with water (20 mL), the solid formed wasfiltered, washed with water and dried. The resulting residue was purifyby chromatography on silica gel (CH₂Cl₂: MeOH; 95:5 v/v) to get thedesired5-fluoro-N4-[2-methyl-2-(N-methylaminocarbonyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.80 (1H, s), 9.44 (1H, s), 9.21 (1H, s), 8.22 (1H,m), 8.18 (1H, d, J=3.9 Hz), 8.06 (1H, m), 7.51-7.41 (3H, m), 7.31 (1H,m), 7.20 (1H, t, J=8.2 Hz), 7.11 (1H, d, J=9 Hz), 5.57 (1H, dd, J=8.1Hz, J=2.7 Hz), 4.46 (2H, s), 2.74 (3H, d, J=4.8 Hz), 2.62 (3H, d, J=4.8Hz), 1.72 (3H, s); LCMS: purity: 94 %; MS (m/e): 510 (MH⁺). 7.4.154N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(N1-methylindazolin-6-yl)-2,4-pyrimidinediamine R940366 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-amino-N1-methylindazole were reacted to yieldN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(N1-methylindazolin-6-yl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ10.74 (1H, s), 9.48 (1H, s),9.42 (1H, s), 8.24 (1H, d, J=3.6 Hz), 8.16 (1H, s), 7.94 (1H, s), 7.63(1H, d, J=8.4 Hz), 7.46 (1H, dd, J=8.4 Hz, J=2.4 Hz), 7.36-7.32 (2H, m),6.99 (1H, d, J=9 Hz), 3.86 (3H, s), 1.50 (6H, s); LCMS: purity: 96.80 %;MS (m/e): 434 (MH⁺). 7.4.155N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940367 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]-oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-amino-2,2-dimethyl-3-oxo-4H-benz[1,4]oxazine were reacted to yieldN4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-(2,2-dimethyl-3-oxo-4H-benz[1,4]-oxazin-3-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.04 (1H, s), 10.64 (1H, s), 9.61 (1H, s), 9.12 (1H,s), 8.17 (1H, d, J=3.6 Hz), 7.54 (1H, dd, J=9 Hz, J=2.7 Hz), 7.55 (1H,d, J=2.7 Hz), 7.32-7.26 (3H, m), 6.87 (1H, d, J=9.3 Hz), 1.46 (6H, s);LCMS: purity: 92.68 %; MS (m/e): 487 (MH⁺). 7.4.156N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamineR940368 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4-oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-amino-1-methylindazole were reacted to yieldN4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ12.09 (1H, s), 9.71 (1H, s),9.49 (1H, s), 8.31 (1H, d, J=3.9 Hz), 8.18 (1H, s), 7.95 (1H, s),7.72-7.69 (1H, m), 7.65 (1H, d, J=9 Hz), 7.59 (1H, m), 7.36 (2H, t,J=8.7 Hz), 3.85 (3H, s); LCMS: purity: 94.55 %; MS (m/e): 442 (MH⁺).7.4.157N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamineR940371 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]-oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-chloro-4-methoxyaniline were reacted to yieldN4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.20 (1H, s), 9.39 (1H, s), 9.34 (1H, s), 8.22 (1H,d, J=3.3 Hz), 7.90 (1H, s), 7.62-7.54 (2H, m), 7.47 (1H, d, J=8.4 Hz),7.08 (1H, d, J=9 Hz), 3.87 (3H, s), 1.53 (6H, s); LCMS: purity: 97.92 %;MS (m/e): 445 (MH⁺). 7.4.158N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamineR940372 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]-oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3,5-dimethoxyaniline were reacted to yieldN4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.15 (1H, s), 9.34 (1H, s), 9.30 (1H, s), 8.23 (1H,d, J=3.3 Hz), 7.74 (1H, dd, J=8.7 Hz, J=3.9 Hz), 7.43 (1H, d, J=8.7 Hz),7.02 (2H, s), 6.16 (1H, s), 3.75 (6H, s), 1.53 (6H, s); LCMS: purity:100 %; MS (m/e): 441 (MH⁺). 7.4.159N2-(3,4-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940373 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]-oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3,4-dichloroaniline were reacted to yieldN2-(3,4-dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.20 (1H, s), 9.68 (1H, s), 9.54 (1H, s), 8.27 (1H,d, J=3.6 Hz), 8.14 (1H, d, J=2.1 Hz), 7.64 (1H, dd, J=8.7 Hz, J=2.1 Hz),7.53-7.47 (3H, m), 1.53 (6H, s); LCMS: purity: 100 %; MS (m/e): 449(M⁺). 7.4.160N4-[(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamineR940380 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-aminoindazole were reacted to yieldN4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.16 (1H, s), 9.48 (1H, s), 9.28 (1H, s), 8.27 (1H,d, J=3.3 Hz), 8.17 (1H, s), 7.98 (1H, s), 7.84 (1H, m), 7.65 (1H, d, J=9Hz), 7.47 (1H, d, J=8.7 Hz), 7.36 (1H, d, J=8.7 Hz), 1.53 (6H, s); LCMS:purity: 100 %; MS (m/e): 421 (MH⁺). 7.4.161N2-(3-tert-Butylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940381 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-tert-butylaniline were reacted to yieldN2-(3-tert-butylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.16 (1H, s), 9.27 (1H, s), 9.23 (1H, s), 8.22 (1H,d, J=3.6 Hz), 7.74 (1H, m), 7.70 (1H, d, J=8.4 Hz), 7.57 (1H, s), 7.44(1H, d, J=8.7 Hz), 7.205 (1H, t, J=7.9 Hz), 7.01 (1H, d, J=7.8 Hz), 1.53(6H, s), 1.33 (9H, s); LCMS: purity: 100 %; MS (m/e): 437 (MH⁺). 7.4.162N4-[(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamineR940382 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-aminophenol were reacted to yieldN4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.16 (1H, s), 9.29 (1H, s), 9.25 (1H, s), 9.23 (1H,s), 8.20 (1H, d, J=3.6 Hz), 7.74 (1H, d, J=8.4 Hz), 7.44 (1H, d, J=8.7Hz), 7.23 (1H, t, J=1.25 Hz), 7.16 (1H, d, J=8.1 Hz), 7.04 (1H, t, J=7.9Hz), 6.40 (1H, dd, J=6.9 Hz, J=1.2 Hz), 1.53 (6H, s); LCMS: purity: 100%; MS (m/e): 397 (MH⁺). 7.4.163N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-fluoro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamineR940384 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-fluoro-4-methoxyaniline were reacted to yieldN4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-fluoro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.20 (1H, s), 9.42 (1H, s), 9.35 (1H, s), 8.21 (1H,d, J=3.6 Hz), 7.75 (1H, dd, J=14.4 Hz, J=2.4 Hz), 7.56 (1H, d, J=8.1Hz), 7.46 (1H, d, J=8.7 Hz), 7.37 (1H, d, J=9.6 Hz), 7.08 (1H, t, J=9.3Hz), 3.85 (3H, s), 1.53 (6H, s); LCMS: purity: 97 %; MS (m/e): 429(MH⁺). 7.4.164N2-(3-Chlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940386 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-chloroaniline were reacted to yieldN2-(3-chlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.10 (1H, s), 9.50 (1H, s), 9.43 (1H, s), 8.16 (1H,d, J=3.3 Hz), 7.85 (1H, t, J=1.95 Hz), 7.47 (2H, d, J =8.7 Hz), 7.38(1H, d, J=8.7 Hz), 7.18 (1H, t, J=8.1 Hz), 6.89 (1H, ddd, J=7.8 Hz,J=2.1 Hz, J=1.2 Hz), 1.43 (6H, s); LCMS: purity: 100 %; MS (m/e): 415(MH⁺). 7.4.165N2-(3,5-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940387 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3,5-dichloroaniline were reacted to yieldN2-(3,5-dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.10 (1H, s), 9.66 (1H, s), 9.49 (1H, s), 8.19 (1H,m), 7.70 (2H, m), 7.39 (2H, m), 6.99 (1H, t. J=1.95 Hz), 1.42 (6H, s);LCMS: purity: 96 %; MS (m/e): 450 (MH⁺). 7.4.166N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine R940389 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-amino-1-methylindazole were reacted to yieldN4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.22 (1H, s), 9.60 (1H, s), 9.43 (1H, s), 8.29 (1H,d, J=3.6 Hz), 8.13 (1H, s), 7.95 (1H, s), 7.72 (1H, d, J=8.4 Hz), 7.64(1H, d, J=9 Hz), 7.47 (1H, d, J=8.1 Hz), 7.34 (1H, dd, J=8.7 Hz, J=1.8Hz), 3.19 (3H, s), 1.53 (6H, s); LCMS: purity: 100 %; MS (m/e): 435(MH⁺). 7.4.167N2-(3-Chloro-4-trifluoromethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940390 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-chloro-4-trifluoromethoxyaniline were reacted to yieldN2-[3-chloro-4-trifluoromethoxyphenyl]-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.24 (1H, s), 9.76 (1H, s), 9.60 (1H, s), 8.28 (1H,d, J=3.6 Hz), 8.14 (1H, d, J=2.4 Hz), 7.70 (1H, dd, J=9 Hz, J=2.7 Hz),7.54-7.43 (3H, m), 1.53 (6H, s); LCMS: purity: 94.6 %; MS (m/e): 499(MH⁺). 7.4.168N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940391 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-chloro-4-methoxy-5-methylaniline were reacted to yieldN2-(3-chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.20 (1H, s), 9.24 (1H, s), 9.40 (1H, s), 8.23 (1H,dd, J=3.3 Hz, J=0.9 Hz), 7.76 (1H, d, J=2.7 Hz), 7.61 (1H, d, J=8.4 Hz),7.47 (1H, d, J=8.1 Hz), 7.42 (1H, d, J=2.7 Hz), 3.76 (3H, d, J=1.2 Hz),2.27 (3H, s), 1.53 (6H, s); LCMS: purity: 100 %; MS (m/e): 459 (MH⁺).7.4.169N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineR940392 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-(methoxycarbonylmethyleneoxy)aniline were reacted to yieldN4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.16 (1H, s), 9.36 (1H, s), 9.34 (1H, s), 8.23 (1H,d, J=3.3 Hz), 7.69 (1H, d, J=8.7 Hz), 7.47 (1H, d, J=8.7 Hz), 7.42 (1H,s), 7.37 (1H, d, J=8.1 Hz), 7.17 (1H, t, J=8.1 Hz), 6.53 (1H, dd, J=8.4Hz, J=2.4 Hz), 4.78 (2H, s), 3.79 (3H, s), 1.53 (6H, s); LCMS: purity:94.69 %; MS (m/e): 469 (MH⁺). 7.4.170N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineR940393 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and4-amino-2-chloro-6-methylphenol were reacted to yieldN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.19 (1H, d, J=1.5 Hz), 9.05 (1H, s), 8.64 (1H, s),8.10 (1H, d, J=3.9 Hz), 7.62 (1H, d, J=2.7 Hz), 7.36 (1H, d, J=1.8 Hz),7.31 (1H, m), 7.27 (1H, d, J=2.7 Hz), 6.87 (1H, d, J=8.4 Hz), 4.31 (4H,s), 2.22 (3H, s); LCMS: purity: 96.98%; MS (m/e): 403 (MH⁺). 7.4.171N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940394 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 4-amino-2-chloro-6-methylphenol were reacted to yieldN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.16 (1H, s), 9.27 (1H, s), 9.15 (1H, s), 8.67 (1H,s), 8.19 (1H, d, J=3.6 Hz), 7.64 (2H, m), 7.42 (1H, d, J=8.4 Hz), 7.29(1H, d, J=2.7 Hz), 2.22 (3H, s), 1.53 (6H, s); LCMS: purity: 97.69%; MS(m/e): 444 (M⁺). 7.4.172N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamineR940395 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3,5-dimethyl-4-methoxyaniline were reacted to yieldN2-(3,5-dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.16 (1H, s), 9.23 (1H, s), 9.11 (1H, s), 8.19 (1H,d, J=3.6 Hz), 7.69 (1H, d, J=8.1 Hz), 7.44 (1H, d, J=8.4 Hz), 7.33 (2H,s), 3.68 (3H, s), 2.23 (6H, s), 1.53 (6H, s); LCMS: purity: 99%; MS(m/e): 439 (MH⁺). 7.4.173N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineR940396 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3,5-dimethyl-4-methoxyaniline were reacted to yieldN2-(3,5-dimethyl-4-methoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.06 (1H, s), 9.85 (1H, s), 8.25 (1H, d, J=4.8 Hz),7.33 (1H, d, J=2.4 Hz), 7.24 (2H, s), 7.20 (1H, d, J=2.7 Hz), 6.91 (1H,d, J=8.4 Hz), 4.32 (4H, s), 3.71 (3H, s), 2.25 (6H, s); LCMS: purity:96.69%; MS (m/e): 397 (MH⁺). 7.4.174N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineR940397 In like manner to the preparation ofN2-(3-chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and3-chloro-5-methyl-4-metoxyaniline were reacted to yieldN2-(3-chloro-4-methoxy-5-methylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.88 (2H, broad s), 8.26 (1H, d, J=4.2 Hz), 7.64 (1H,s), 7.41 (1H, s), 7.30-7.28 (1H, m), 7.25-7.20 (1H, m), 6.92 (1H, d,J=10.2 Hz), 4.32 (4H, s), 3.79 (3H, s), 2.29 (3H, s); LCMS: purity:94.81%; MS (m/e): 417 (MH⁺). 7.4.1755-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(N-morpholino)carbonyl-4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine(R950411) A solution ofN4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DMF was treated with PyBroP and morpholine. The mixture was stirredfor 1 hour at 22° C. and purified by flash chromatography on silica gelto give5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(N-morpholino)carbonyl-4-trifluoromethoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.62 (s, 1H), 9.29 (s, 1H),7.77-8.17 (m, 7H), 7.12 (t, 1H, J=8.1 Hz), 6.48 (m, 1H), 4.36 (s, 2H),3.02-4.36 (m, 8H), 2.64 (s, 3H); LCMS: purity: 92.9%; MS (m/e): 565.34(MH⁺). 7.4.176N4-[3-(N-2-Aminoethylamino)carbonyl-4-trifluoromethoxyphenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950406) A solution ofN4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DMF was treated with PyBroP and 1,2-diaminoethane. The mixture wasstirred for 1 hour at 22° C. and purified by flash chromatography onsilica gel to giveN4-[3-(N-2-aminoethylamino)carbonyl-3-trifluoromethoxyphenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 100%; MS (m/e): 538.5 (MH⁺). 7.4.1775-Fluoro-N4-[3-(N-methylamino)carbonyl-4-trifluoromethoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950407) A solution ofN4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DMF was treated with PyBroP and N-methylamine. The mixture wasstirred for 1 hour at 22° C. and purified by flash chromatography onsilica gel to give5-fluoro-N4-[3-(N-methylamino)carbonyl-4-trifluoromethoxyphenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 93.3%; MS (m/e): 496.27 (MH⁺). 7.4.1785-Fluoro-N4-(3-[N-(2-(N-methylamino)ethyleneamino)carbonyl-4-trifluoromethoxyphenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950408) A solution ofN4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DMF was treated with PyBroP and N1-methylamino-2-aminoethane. Themixture was stirred for 1 hour at 22° C. and purified by flashchromatography on silica gel to give5-fluoro-N4-(3-[N-(2-(N-methylamino)ethyleneamino)carbonyl-4-trifluoromethoxyphenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 81.6%; MS (m/e): 552.37 (MH⁺). 7.4.1795-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(N-piperidinocarbonyl-4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine(R950409)5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(N-piperidinocarbonyl-4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine(R950409) A solution ofN4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DMF was treated with PyBroP and piperidine. The mixture was stirredfor 1 hour at 22° C. and purified by flash chromatography on silica gelto give5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(N-piperidinocarbonyl-4-trifluoromethoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 90.4%; MS (m/e): 563.36 (MH⁺). 7.4.180(R)-N4-(3-[N-(1,2-Dihydroxyproypylamino)carbonyl-4-trifluoromethoxyphenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950410) A solution ofN4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein DMF was treated with PyBroP and (R)-1,2-dihydroxypropylamine. Themixture was stirred for 1 hour at 22° C. and purified by flashchromatography on silica gel to give(R)-N4-(3-[N-(1,2-dihydroxyproypylamino)carbonyl-4-trifluoromethoxyphenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 82.6%; MS (m/e): 569.34 (MH⁺). 7.4.181(±) 4-(N-tert-Butoxycarbonyl)amino-6-nitro-1-benzopyran A solution of(±) 4-amino-6-nitro-1-benzopyran in dioxane-water was treated withdi-tert-butyl carbonate and sodium bicarbonate. The mixture was stirredfor 2 hours at 0° C. and diluted with hexane. The mixture was filtered,and the remaining solids were carefully washed with hexane and driedunder reduced pressure to give (±)4-(N-tert-butoxycarbonyl)amino-6-nitro-1-benzopyran as a pale yellowsolid. ¹H NMR (CDCl₃): δ8.23 (d, 1H, J=2.7 Hz), 8.04 (dd, 1H, J=2.7, 9.6Hz), 6.88 (d, 1H, J=9.6 Hz), 4.89 (bs, 1H), 4.81 (bs, 1H), 4.26-4.38 (m,2H), 2.03-2.26 (m, 2H). 7.4.182 (±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl)-2-chloro-5-fluoro-2,4-pyrimidineamineA mixture (±) 4-(N-tert-butoxycarbonyl)amino-6-nitro-1-benzopyran andPd/C (10%) in MeOH was hydrogenated at 22° C. for 3 hours (40 psi). Themixture was filtered and concentrated to dryness to give6-amino-4-(N-tert-butoxycarbonyl)amino-1-benzopyran as a brown oil. Theresulting oil of 6-amino-4-(N-tert-butoxycarbonyl)amino-1-benzopyran wasreacted with 2,4-dichloro-5-fluoro-pyrimidine in MeOH at 70° C. for 2hours. The reaction mixture was diluted with water and the resultingprecipitate was filtered to give (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl)-2-chloro-5-fluoro-2,4-pyrimidineamineas a pale yellow solid. ¹H NMR (DMSO-d₆): δ9.85 (s, 1H), 8.22 (d, 1H,J=2.4 Hz), 7.38 (m, 3H), 6.75 (d, 1H, J=9.6 Hz), 4.15-4.72 (m, 3H),1.88-2.01 (m, 2H), 1.42 (s, 9H); LCMS: purity: 92.3%; MS (m/e): 397.02(MH⁺). 7.4.183 (±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950405) A solution of equimolar amount of (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl)-2-chloro-5-fluoro-2,4-pyrimidineamineand 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH and heated in asealed tube at 110° C. for 24 hours. The resulting reaction mixture wasdiluted with water and the solid was isolated by fitration to give (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.24 (s, 1H), 9.04 (s, 1H), 8.01(d, 1H, J=2.4 Hz), 7.93 (d, 1H, J=4.5 Hz), 7.60 (d, 1H, J=7.2 Hz),7.22-7.36 (m, 3H), 7.07 (t, 1H, J=8.4 Hz), 6.69 (d, 1H, J=9.0 Hz), 6.56(m, 1H), 4.70 (m, 1H), 4.29 (s, 2H), 4.17 (m, 2H), 2.64 (s, 3H),1.88-2.08 (m, 2H), 1.40 (s, 9H); LCMS: purity: 93.7%; MS (m/e): 537.28(M⁻). 7.4.184 (±)4-(N-tert-Butoxycarbonyl-N-methyl)amino-6-nitro-1-benzopyran A solutionof 4-amino-6-nitro-1-benzopyran in THF was treated with sodium hydridefollowed by methyl iodide. The mixture was stirred for 24 hours at 0° C.The mixture was diluted with water and extracted with dichloromethane.The organic phase was dried over magnesium sulfate and concentratedunder reduced pressure to give (±)4-(N-tert-butoxycarbonyl-N-methyl)amino-6-nitro-1-benzopyran as a paleyellow solid. ¹H NMR (CDCl₃): δ7.98 (dd, 1H, J=3.4, 9.3 Hz), 7.90 (bs,1H), 6.82 (d, 1H, J=9.3 Hz), 5.65 (bs, 1H), 4.18-4.44 (m, 2H), 1.98-2.06(m, 2H), 2.55 (s, 3H). 7.4.185 (±)N4-[4-(N-tert-Butoxycarbonyl-N-methyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-2,4-pyrimidineamineA mixture (±)4-(N-tert-butoxycarbonyl-N-methyl)amino-6-nitro-1-benzopyran and Pd/C(10%) in MeOH was hydrogenated at 22° C. for 3 hours (40 psi). Themixture was filtered and concentrated to dryness to give6-amino-4-(N-tert-butoxycarbonyl-N-methyl)amino-1-benzopyran as a brownoil. The resulting (±)6-amino-4-(N-tert-butoxycarbonyl-N-methyl)amino-1-benzopyran was reactedwith 2,4-dichloro-5-fluoro-pyrimidine in MeOH at 70° C. for 2 hours. Themixture was diluted with water and the resulting precipitate wasfiltered to give (±)N4-[4-(N-tert-butoxycarbonyl-N-methyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-2,4-pyrimidineamineas a pale yellow solid. LCMS: purity: 88.0%; MS (m/e): 408.14 (M⁻).7.4.186 (±)5-Fluoro-N4-[4-(N-methyl)amino-1-benzopyran-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950412) A solution of equimolar amount of (±)N4-[4-(N-tert-butoxycarbonyl-N-methyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-2,4-pyrimidineamineand 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH was heated in asealed tube in the presence of a catalytic amount of trifluoroaceticacid at 110° C. for 24 hours. The reaction mixture was diluted withwater and the solid was isolated by filtration to give (±)5-fluoro-N4-[(4-N-methyl)amino-1-benzopyran-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.62 (s, 1H), 9.46 (s, 1H), 8.71 (bs, 3H), 8.01-8.12(m, 3H), 7.47 (s, 1H), 7.39(m, 1H), 7.27 (d, 1H, J=7.2 Hz), 7.11 (t, 1H,J=7.2 Hz), 6.86 (d, 1H, J 7.0 Hz), 6.46 (m, 1H), 4.20-4.46 (m, 3H), 4.31(s, 3H), 2.64 (d, 3H, J=4.8 Hz), 2.55 (s, 3H), 2.05-2.19 (m, 2H); LCMS:purity: 94.8%; MS (m/e): 451.17 (M⁻). 7.4.187 (±)N4-[4-(N-tert-Butoxycarbonyl-N-methyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950415) A solution of equimolar amount of (±)N4-[4-(N-tert-butoxycarbonyl-N-methyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-2,4-pyrimidineamineand 3-(N-methylamino)carbonylmethyleneoxyaniline in MeOH was heated in asealed tube at 80° C. for 7 days. Aqueous work up gave (±)N4-[4-(N-tert-butoxycarbonyl-N-methyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ10.22-10.34 (m, 2H), 8.23 (d, 1H,J=5.1 Hz), 7.99 (d, 1H, J=4.2 Hz), 6.98-7.56 (m 3H), 6.74 (d, 1H, J=9.0Hz), 6.65 (d, 1H, J=7.8 Hz), 5.41 (bs, 1H), 5.18 (bs, 1H), 4.15-4.36 (m,5H), 2.63 (s, 3H), 1.90-2.20 (m, 2H), 1.44 (s, 9H); LCMS: purity: 97.3%;MS (m/e): 551.25 (M⁻). 7.4.188 (±)4-(N-Acetyl)amino-6-nitro-1-benzopyran A solution of4-hydroxy-6-nitro-1-benzopyran in dry acetonitrile was treated withconcentrated sulfuric acid. The mixture was stirred for 1 hour at 22° C.to give (±) 4-(N-acetyl)amino-6-nitro-1-benzopyran as a pale brownishprecipitate, which was filtered off and dried. ¹H NMR (CDCl₃): δ8.13 (d,1H, J=2.8 Hz), 8.04 (dd, 1H, J=2.8, 8.7 Hz), 6.88 (d, 1H, J=8.7 Hz),5.87 (bs, 1H), 5.17-5.24 (m, 1H), 4.25-4.39 (m, 2H), 2.04-2.26 (m, 2H),2.08 (s, 3H). 7.4.189 (±) 4-Amino-6-nitro-1-benzopyran A solution of (±)4-(N-acetyl)amino-6-nitro-1-benzopyran in concentrated HCl was refluxedfor 16 hours. The reaction mixture was concentrated to dryness underreduced pressure and basified by addition of potassium carbonate. Waterwas added and the aqueous phase was extracted with methylene chlorideand dried over magnesium sulfated. Removal of the volatiles underreduced pressure gave (±) 4-amino-6-nitro-1-benzopyran as a yellowsolid, which used in the next step without further purification. ¹H NMR(CDCl₃): δ8.23 (d, 1H, J=3.0 Hz), 7.96 (dd, 1H, J=3.0, 9.0 Hz), 6.80 (d,1H, J=9.0 Hz), 4.04-4.41 (m, 3H), 1.78-2.14 (m, 2H). 7.4.190(S)-4-Amino-6-nitro-1-benzopyran (L)-(+)-Tartaric Acid Salt A solutionof (±)-4-amino-6-nitro-1-benzopyran in ethanol-water was treated withL-(+)-tartaric acid and heated to give a clear solution. The mixture waskept for 3 days at 22° C. and the resulting precipitate was filtered andwashed carefully with ethanol to give enantiomerically pure(S)-4-amino-6-nitrobenzo-1-pyran (L)-(+)-tartaric acid salt. ¹H NMR(DMSO-d₆): δ8.44 (d, 1H, J=2.7 Hz), 8.08 (dd, 1H, J=2.7, 9.3 Hz), 7.01(d, 1H, J=9.3 Hz), 4.32-4.39 (m, 3H), 3.97 (s, 2H), 1.90-2.26 (m, 2H).7.4.191 (R)-4-Amino-6-nitro-1-benzopyran (D)-(−)-Tartaric Acid Salt Asolution of (±)-4-amino-6-nitrobenzopyran in ethanol-water was treatedwith D-(−)-tartaric acid and heated to give a clear solution. Themixture was kept for 3 days at 22° C. and the resulting precipitate wasfiltered and washed carefully with ethanol to give enantiomerically pure(R)-4-amino-6-nitro-1-benzopyran (D)-(−)-tartaric acid salt. ¹H NMR(DMSO-d₆): δ8.44 (d, 1H, J=2.7 Hz), 8.08 (dd, 1H, J=2.7, 9.3 Hz), 7.01(d, 1H, J=9.3 Hz), 4.32-4.39 (m, 3H), 3.97 (s, 2H), 1.90-2.26 (m, 2H).7.4.192(S)-N4-[4-(N-Benzyloxycarbonyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine(R950413) A solution of (S)-4-amino-6-nitro-1-benzopyran indioxane-water was treated with benzylchloroformate and sodiumbicarbonate. The mixture was stirred for 1 hour at 0° C. and dilutedwith hexane. The mixture was filtered, and the remaining solid wascarefully washed with hexane and dried under reduced vacuum to give(S)-4-(N-benzyloxycarbonyl)amino-6-nitro-1-benzopyran as a pale yellowsolid. The crude material was dissolved in EtOH and treated with ironpowder and ammonium chloride. The mixture was stirred for 2 hours at 85°C. and filtered to give a clear solution, which was diluted with water.The aqueous phase was extracted with dichloromethane and the organicphase was dried over magnesium sulfate. Removal of the volatiles underreduced pressure gave(S)-6-amino-4-(N-benzyloxycarbonyl)amino-1-benzopyran as a brown oil.The reaction of (S)-6-amino-4-(N-benzyloxycarbonyl)amino-1-benzopyranwith 2,4-dichloro-5-fluoropyrimidine in MeOH for 2 hours at 70° C.followed by dilution with water and fitration of the resulting residuegave(S)-2-chloro-N4-[4-(N-benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-4-pyrimidineamineas a pale yellow solid. ¹H NMR (DMSO-d₆): δ9.87 (s, 1H), 9.23 (d, 1H,J=2.4 Hz), 7.85 (d, 1H, J=9.0 Hz), 7.25-7.45 (m, 7H), 6.77 (d, 1H, J=8.4Hz), 5.08 (s, 2H), 4.78 (bs, 1H), 4.19 (s, 2H), 1.93-2.06 (m, 2H); LCMS:purity: 97.2%; MS (m/e): 429.4 (MH⁺). 7.4.193(R)-2-Chloro-N4-[4-(N-benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-4-pyrimidineamine(R950413) A solution of (R)-4-amino-6-nitro-1-benzopyran indioxane-water was treated with benzylchloroformate and sodiumbicarbonate. The mixture was stirred for 1 hour at 0° C. and dilutedwith hexane. The mixture was filtered, and the remaining solid wascarefully washed with hexane and dried under reduced vacuum to give(R)-4-(N-benzyloxycarbonyl)amino-6-nitro-1-benzopyran as a pale yellowsolid. The crude material was dissolved in EtOH and treated with ironpowder and ammonium chloride. The mixture was stirred for 2 hours at 85°C. and filtered to give a clear solution, which was diluted with water.The aqueous phase was extracted with dichloromethane and the organicphase was dried over magnesium sulfate. Removal of the volatiles underreduced pressure gave(R)-6-amino-4-(N-benzyloxycarbonyl)amino-1-benzopyran as a brown oil.The reaction of (R)-6-amino-4-(N-benzyloxycarbonyl)amino-1-benzopyranwith 2,4-dichloro-5-fluoropyrimidine in MeOH for 2 hours at 70° C.followed by dilution with water and fitration of the resulting residuegave(R)-2-chloro-N4-[4-(N-benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-4-pyrimidineamineas a pale yellow solid. ¹H NMR (DMSO-d₆): δ9.87 (s, 1H), 9.23 (d, 1H,J=2.4 Hz), 7.85 (d, 1H, J=9.0 Hz), 7.25-7.45 (m, 7H), 6.77 (d, 1H, J=8.4Hz), 5.08 (s, 2H), 4.78 (bs, 1H), 4.19 (s, 2H), 1.93-2.06 (m, 2H); LCMS:purity: 96.1%; MS (m/e): 429.4 (MH⁺). 7.4.194(S)-N4-[4-(N-Benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950417)(S)-2-chloro-N4-[4-(N-benzyloxycarbonyl)amino-1-benzopyran-6-yl)-5-fluoro-4-pyrimidineamineand equimolar amounts of 3-(N-methylamino)carbonylmethyleneoxyanilinewere dissolved in MeOH and heated in a sealed tube at 110° C. for 24hours. Aqueous work up gave(S)-N4-[4-(N-benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.83 (bs, 1H), 9.58 (bs, 1H), 8.12(d, 1H, J=2.4 Hz), 7.94 (m, 1H), 7.80 (d, 1H, J=8.7 Hz), 7.56 (m, 1H),7.11-7.36 (m, 8H), 6.72 (d, 1H, J=8.7 Hz), 6.56 (m, 1H), 5.04 (m, 2H),4.79 (m, 1H), 4.17-4.30 (m, 4H), 2.63 (s, 3H), 1.91-2.08 (m, 2H); LCMS:purity: 93.6%; MS (m/e): 571.26 (M⁻). 7.4.195(R)-N4-[4-(N-Benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950418)(R)-2-chloro-N4-[4-(N-benzyloxycarbonyl)amino-1-benzopyran-6-yl)-5-fluoro-4-pyrimidineamineand equimolar amounts of 3-(N-methylamino)carbonylmethyleneoxyanilinewere dissolved in MeOH and heated in a sealed tube at 110° C. for 24hours. Aqueous work up gave(R)-N4-[4-(N-benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid.¹H NMR (DMSO-d₆): δ9.83 (bs, 1H), 9.58 (bs, 1H), 8.12(d, 1H, J=2.4 Hz), 7.94 (m, 1H), 7.80 (d, 1H, J=8.7 Hz), 7.56 (m, 1H),7.11-7.36 (m, 8H), 6.72 (d, 1H, J=8.7 Hz), 6.56 (m, 1H), 5.04 (m, 2H),4.79 (m, 1H), 4.17-4.30 (m, 4H), 2.63 (s, 3H), 1.91-2.08 (m, 2H); LCMS:purity: 92.5%; MS (m/e): 571.26 (M⁻). 7.4.196(S)-N4-(4-Amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950420)(S)-N4-[4-(N-Benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand Pd/C 10% (50% water content) were suspended in MeOH and hydrogenatedin a Parr apparatus for 14 hours (22° C., 40 psi). The suspension wasfiltered over celite and washed with MeOH. The combined filtrates wereconcentrated under reduced pressure to give(S)-N4-(4-amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.60 (s, 1H), 9.46 (s, 1H), 8.73(bs, 3H), 8.00-8.10 (m, 3H), 7.47 (s, 1H), 7.42 (m, 1H), 7.29 (d, 1H,J=7.2 Hz), 7.11 (t, 1H, J=7.2 Hz), 6.82 (d, 1H, J 7.0 Hz), 6.46 (m, 1H),4.23-4.46 (m, 3H), 4.31 (s, 3H), 2.63 (d, 3H, J=4.8 Hz), 2.09-2.29 (m,2H); LCMS: purity: 98.1%; MS (m/e): 437.20 (M⁻). 7.4.197(R)-N4-(4-Amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950421)(R)-N4-[4-(N-Benzyloxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand Pd/C 10% (50% water content) were suspended in MeOH and hydrogenatedin a Parr apparatus for 14 hours (22° C., 40 psi). The suspension wasfiltered over celite and washed with MeOH. The combined filtrates wereconcentrated under reduced pressure to give(R)-N4-(4-amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.60 (s, 1H), 9.46 (s, 1H), 8.73(bs, 3H), 8.00-8.10 (m, 3H), 7.47 (s, 1H), 7.42 (m, 1H), 7.29 (d, 1H,J=7.2 Hz), 7.11 (t, 1H, J=7.2 Hz), 6.82 (d, 1H, J 7.0 Hz), 6.46 (m, 1H),4.23-4.46 (m, 3H), 4.31 (s, 3H), 2.63 (d, 3H, J=4.8 Hz), 2.09-2.29 (m,2H); LCMS: purity: 98.6%; MS (m/e): 437.20 (M⁻). 7.4.198 (±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine(R950422) A mixture of equimolar amounts of (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-4-pyrimidineamineand 6-aminoindazole in MeOH was stirred in a sealed tube for 24 hours at100° C. Aqueous work up gave a brown solid which was further purified bycolumn chromatography on silica gel to give (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamineas a white solid. LCMS: purity: 92.7%; MS (m/e): 490.23 (M⁻). 7.4.199(±)N4-(4-Amino-1-benzopyran-6-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine(R950423) (±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to give (±)N4-(4-amino-1-benzopyran-6-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.0%; MS (m/e): 390.21 (M⁻). 7.4.200(±)N4-(4-Amino-1-benzopyran-6-yl)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950424) A mixture of equimolar amounts of (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-4-pyrimidineamineand the HCl salt of 3,5-dichloro-4-methoxyaniline in MeOH was stirred ina sealed tube for 24 hours at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togive (±)N4-(4-amino-1-benzopyran-6-yl)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.42 (s, 1H), 9.33 (s, 1H), 8.08(d, 1H, J=2.4 Hz), 7.76 (s, 2H), 7.61 (m, 1H), 7.36 (d, 1H, J=2.7, 8.4Hz), 6.78 (d, 1H, J=8.7 Hz), 3.72-4.23 (m, 3H), 3.72 (s, 3H), 1.85-2.18(m, 2H); LCMS: purity: 97.3%; MS (m/e): 448.12 (M⁻). 7.4.201 (±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950425) A mixture of equimolar amounts of (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-4-pyrimidineamineand 3,5-dimethoxyaniline in MeOH was stirred in a sealed tube for 24hours at 100° C. Aqueous work up gave a brown solid which was furtherpurified by column chromatography on silica gel to give (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.24 (s, 1H), 8.96 (s, 1H), 8.02(d, 1H, J=2.4 Hz), 7.61 (m, 1H), 7.28 (m, 2H), 6.91 (s, 2H), 6.68 (d,1H, J=8.7 Hz), 6.03 (m, 1H), 4.68 (m, 1H), 4.17 (m, 2H), 1.80-2.05 (m,2H), 1.41 (s, 9H); LCMS: purity: 93.9%; MS (m/e): 510.24 (M⁻). 7.4.202(±)N4-(4-Amino-1-benzopyran-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950426) (±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to giveN4-(4-amino-1-benzopyran-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. LCMS: purity: 93.1%; MS (m/e): 410.23 (M⁻). 7.4.203(±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950427) A mixture of equimolar amounts of (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-4-pyrimidineamineand 3-chloro-4-methoxyaniline in MeOH was stirred in a sealed tube for24 hours at 100° C. Aqueous work up gave a brown solid which was furtherpurified by column chromatography on silica gel to give (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. LCMS: purity: 93.7%; MS (m/e): 514.21 (M⁻). 7.4.204(±)N4-(4-Amino-1-benzopyran-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950428) (±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to give (±)N4-(4-amino-1-benzopyran-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 91.4%; MS (m/e): 414.13 (M⁻). 7.4.205 (±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3,4-dichlorophenyl)-5-fluoro2,4-pyrimidinediamine (R950429) A mixture of equimolar amounts of (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-2-chloro-5-fluoro-4-pyrimidineamineand 3,4-dichloroaniline in MeOH was stirred in a sealed tube for 24hours at 100° C. Aqueous work up gave a brown solid which was furtherpurified by column chromatography on silica gel to give (±)N4-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3,4-dichlorophenyl)-5-fluoro2,4-pyrimidinediamine as a white solid. LCMS: purity: 86.7%; MS (m/e):518.17 (M⁻). 7.4.206 (±)N4-(4-Amino-1-benzopyran-6-yl)-N2-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950430) (±)N4-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N2-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to give (±)N4-(4-amino-1-benzopyran-6-yl)-N2-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. LCMS: purity: 88.3%; MS (m/e): 418.16 (M⁻). 7.4.207(±)N2-[4-(N-tert-Butoxycarbonylamino-1-benzopyran-6-yl]-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950432) A mixture of equimolar amounts of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine and (±)6-amino-4-(N-tert-butoxycarbonyl)amino-1-benzopyran in MeOH was stirredin a sealed tube for 24 hours at 100° C. Aqueous work up gave a brownsolid which was further purified by column chromatography on silica gelto give (±)N2-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. LCMS: purity: 97.2%; MS (m/e): 510.3 (M⁻). 7.4.208 (±)N2-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950433) A mixture of equimolar amounts of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and (±)6-amino-4-(N-tert-butoxycarbonyl)amino-1-benzopyran in MeOH was stirredin a sealed tube for 24 hours at 100° C. Aqueous work up gave a brownsolid which was further purified by column chromatography on silica gelto give (±)N2-[4-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.51 (s, 1H), 9.12 (s, 1H), 8.12(d, 1H. J=2.4 Hz), 8.06 (d, 1H, J=3.6 Hz), 7.82 (m, 1H), 7.49 (d, 1H,J=8.7 Hz), 7.43 (m, 1H), 7.32 (d, 1H, J=9.0 Hz), 7.25 (m, 1H), 6.67 (d,1H, J=8.7 Hz), 4.12-4.65 (m, 3H), 1.84-1.99 (m, 2H), 1.40 (s, 9H); LCMS:purity: 97.2%; MS (m/e): 518.3 (M⁻). 7.4.209N2-[4(R,S)-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N4-[2-(S)-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine(R950434) A mixture of equimolar amounts of(S)-2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand (±) 6-amino-4-(N-tert-butoxycarbonyl)amino-1-benzopyran in MeOH wasstirred in a sealed tube for 24 hours at 100° C. Aqueous work up gave abrown solid which was further purified by column chromatography onsilica gel to giveN2-[4-(R,S)-(N-tert-butoxycarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N4-[2-(S)-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 89.3%; MS (m/e): 537.42 (MH⁺). 7.4.210(±)N2-(4-Amino-1-benzopyran-6-yl]-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950436) (±)N2-[4-(N-tert-Butoxycarbonylamino-1-benzopyran-6-yl]-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to give (±)N2-(4-amino-1-benzopyran-6-yl]-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 92.4%; MS (m/e): 410.17 (M⁻). 7.4.211 (±)N2-(4-Amino-1-benzopyran-6-yl)-N4-(3,4-dichlorophenyl)-5-fluoro2,4-pyrimidinediamine (R950437) (±)N2-[4-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to give (±)N2-(4-amino-1-benzopyran-6-yl)-N4-(3,4-dichlorophenyl)-5-fluoro2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ9.51 (s, 1H), 8.99 (s, 1H),8.09 (d, 1H, J=2.4 Hz), 8.07 (d, 1H, J=3.6 Hz), 7.45-7.81 (m, 2H), 7.30(dd, 1H, J=2.4, 9.0 Hz), 6.62 (d, 1H, J=8.7 Hz), 3.78-4.20 (m, 3H),1.73-2.05 (m, 2H); LCMS: purity: 100%; MS (m/e): 420.29 (M⁻, 100).7.4.213N2-[4(R,S)-Amino-1-benzopyran-6-yl)-5-fluoro-N4-(2(S)-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine(R950438) N2-[4(R,S)-(N-tert-Butoxycarbonyl)amino-1-benzopyran-6-yl]5-fluoro-N4-(2(S)-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine wassuspended in dichloromethane and treated with trifluoroacetic acid. Themixture was stirred for 30 minutes at 22° C. and concentrated to drynessunder reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to giveN2-[4(R,S)-amino-1-benzopyran-6-yl)-5-fluoro-N4-(2(S)-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine.LCMS: purity: 97.9%; MS (m/e): 435.37 (M⁻). 7.4.214N2-[(1R,2R)-2-Aminocyclohex-1-yl)-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950439) A mixture of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine and 5equivalents of (R,R)-1,2-diaminocyclohexane in MeOH was stirred in asealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togiveN2-[(1R,2R)-2-aminocyclohex-1-yl)-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 94.6%; MS (m/e): 360.20 (M⁻). 7.4.215N2-[(1R,2R)-2-Aminocyclohex-1-yl)-N4-(3,5-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950440) A mixture ofN4-(3,4-dichlorophenyl)-2-chloro-5-fluoro-4-pyrimidineamine and 5equivalents of (R,R)-1,2-diaminocyclohexane in MeOH was stirred in asealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togiveN2-[(1R,2R)-2-aminocyclohex-1-yl)-N4-(3,5-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.49 (s, 1H), 9.26 (s, 1H), 8.02, 7.44-7.54 (m, 3H),6.81 (d, 1H, J=9.0 Hz), 3.31 (m, 1H), 2.78 (m, 1H), 1.15-1.98 (m, 8H);LCMS: purity: 98.3%; MS (m/e): 368.07 (M⁻, 100). 7.4.216N2-((1R,2R)-2-Aminocyclohex-1-yl)-5-fluoro-N4-[(2S)-2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R950441) A mixture of(S)-2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 5 equivalents of (R,R)-1,2-diaminocyclohexane in MeOH was stirred ina sealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togiveN2-((1R,2R)-2-aminocyclohex-1-yl)-5-fluoro-N4-[(2S)-2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.LCMS: purity: 91.8%; MS (m/e): 385.15 (M⁻). 7.4.217(R,R)-N4-(4,4-Dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-(2-aminocyclohexan-1-yl)-2,4-pyrimidinediamine(R950442) A mixture ofN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-2-chloro-5-fluoro-4-pyrimidineamineand 5 equivalents of (R,R)-1,2-diaminocyclohexane in MeOH was stirred ina sealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togive(R,R)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-(2-aminocyclohexan-1-yl)-2,4-pyrimidinediamineLCMS: purity: 92.1%; MS (m/e): 411.14 (M⁻). 7.4.218N2-((1R,2R)-2-Aminocyclohex-1-yl)-5-fluoro-N4-[(2R,S)-2-(2-hydroxy)ethyl-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine(R950443) An mixture of(±)-2-chloro-N4-[2-(2-hydroxy)ethyl-3-oxo-4H-benz[1,4]oxazin-6-yl]-4-pyrimidineamineand 5 equivalents of (R,R)-1,2-diaminocyclohexane in MeOH was stirred ina sealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togiveN2-((1R,2R)-2-aminocyclohex-1-yl)-5-fluoro-N4-[(2R,S)-2-(2-hydroxy)ethyl-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine.LCMS: purity: 86.1%; MS (m/e): 415.17 (M⁻). 7.4.219N4-(3,5-Dimethoxyphenyl)-N2-[4-(2-N,N-diethylaminoethyleneamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine(R950444) A mixture of equimolar amounts of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine and4-[(2-N,N-diethylaminoethyleneamino)carbonyl]aniline in MeOH was stirredin a sealed tube for 3 days at 100° C. Aqueous work up gave a brownsolid which was further purified by column chromatography on silica gelto giveN4-(3,5-dimethoxyphenyl)-N2-[4-(2-N,N-diethylaminoethyleneamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine. LCMS: purity: 89.1%; MS (m/e): 481.19 (M⁻).7.4.220N4-(3,4-Dichlorophenyl)-N2-[4-(2-N,N-diethylaminoethyleneamino)carbonylphenyl]-5-fluoro2,4-pyrimidinediamine (R950445) A mixture of equimolar amounts of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and4-[(2-N,N-diethylaminoethyleneamino)carbonyl]aniline in MeOH was stirredin a sealed tube for 3 days at 100° C. Aqueous work up gave a brownsolid which was further purified by column chromatography on silica gelto giveN4-(3,4-dichlorophenyl)-N2-[4-(2-N,N-diethylaminoethyleneamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 93.2%; MS (m/e): 489.12 (M⁻). 7.4.221(S)-N2-[4-(2-N,N-Diethylaminoethyleneamino)carbonylphenyl]-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R950446) A mixture of equimolar amounts of(S)-2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 4-[(2-N,N-diethylaminoethyleneamino)carbonyl]aniline in MeOH wasstirred in a sealed tube for 3 days at 100° C. Aqueous work up gave abrown solid which was further purified by column chromatography onsilica gel to give(S)-N2-[4-(2-N,N-diethylaminoethyleneamino)carbonylphenyl]-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.LCMS: purity: 93.9%; MS (m/e): 506.15 (M⁻). 7.4.222N4-(4,4-Dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-[4-(N,N-diethylaminoethylenaminocarbonyl)phenyl]-2,4-pyrimidinediamine(R950447) A mixture of equimolar amounts ofN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-2-chloro-5-fluoro-4-pyrimidineamineand 1-amino-4-(N,N-diethylaminoethylenaminocarbonyl)benzene in MeOH wasstirred in a sealed tube for 3 days at 100° C. Aqueous work up gave abrown solid which was further purified by column chromatography onsilica gel to giveN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-[4-(N,N-diethylaminoethylenaminocarbonyl)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ11.32 (s, 1H), 9.96 (s, 1H), 9.70 (s, 1H), 9.55 (s,1H), 8.66 (m, 1H), 7.67-8.24 (m, 7H), 3.59 (m, 2H), 3.17 (m, 6H), 1.53(s, 6H), 1.22 (t, 6H, J=7.2 Hz); LCMS: purity: 94.7%; MS (m/e): 532.21(M⁻). 7.4.223(±)-N2-[4-(2-N,N-Diethylaminoethyleneamino)carbonylphenyl]-5-fluoro-N4-[(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine(R950448) A mixture of equimolar amounts of(±)-2-chloro-5-fluoro-N4-[(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-4-pyrimidineamineand 4-[(2-N,N-diethylaminoethyleneamino)carbonyl]aniline in MeOH wasstirred in a sealed tube for 3 days at 100° C. Aqueous work up gave abrown solid which was further purified by column chromatography onsilica gel to give(±)-N2-[4-(2-N,N-diethylaminoethyleneamino)carbonylphenyl]-5-fluoro-N4-[(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.LCMS: purity: 93.7%; MS (m/e): 536.17 (M⁻). 7.4.224N2-[4-(2-N,N-Diethylaminoethyleneamino)carbonylphenyl]-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950449) A mixture of equimolar amounts of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidineamineand 4-[(2-N,N-diethylaminoethyleneamino)carbonyl]aniline in MeOH wasstirred in a sealed tube for 3 days at 100° C. Aqueous work up gave abrown solid which was further purified by column chromatography onsilica gel to giveN2-[4-(2-N,N-diethylaminoethyleneamino)carbonylphenyl]-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 86.8%; MS (m/e): 528.18 (M⁻). 7.4.225N2-(4-Aminocarbonylphenyl)-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950450) A mixture of equimolar amounts of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine and4-aminocarbonylaniline in MeOH was stirred in a sealed tube for 3 daysat 100° C. Aqueous work up gave a brown solid which was further purifiedby column chromatography on silica gel to giveN2-(4-aminocarbonylphenyl)-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.34 (s, 1H), 10.14 (s, 1H), 8.30 (d, 1H, J=2.4 Hz),7.75 (d, 2H, J=9.0 Hz), 7.62 (d, 2H, J=8.7 Hz), 7.25-7.35 (m, 2H), 6.90(m, 2H), 6.35 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H); LCMS: purity: 89.2%;MS (m/e): 382.16 (M⁻). 7.4.226N2-(4-Aminocarbonylphenyl)-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950451) A mixture of equimolar amounts of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and4-aminocarbonylaniline in MeOH was stirred in a sealed tube for 3 daysat 100° C. Aqueous work up gave a brown solid which was further purifiedby column chromatography on silica gel to giveN2-(4-aminocarbonylphenyl)-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 93.9%; MS (m/e): 390.09 (M⁻). 7.4.227(S)-N2-(4-Aminocarbonylphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R950452) A mixture of equimolar amounts of(S)-2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 4-aminocarbonylaniline in MeOH was stirred in a sealed tube for 3days at 100° C. Aqueous work up gave a brown solid which was furtherpurified by column chromatography on silica gel to give(S)-N2-(4-aminocarbonylphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.LCMS: purity: 92.3%; MS (m/e): 407.18 (M⁻). 7.4.228N4-(4,4-Dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-(4-aminocarbonylphenyl)-2,4-pyrimidinediamine(R950453) A mixture of equimolar amounts ofN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-2-chloro-5-fluoro-4-pyrimidineamineand 1-amino-4-aminocarbonylbenzene in MeOH was stirred in a sealed tubefor 3 days at 100° C. Aqueous work up gave a brown solid which wasfurther purified by column chromatography on silica gel to giveN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-(4-aminocarbonylphenyl)-2,4-pyrimidinediamineLCMS: purity: 92.2%; MS (m/e): 433.17 (M⁻). 7.4.229(±)-N2-(4-Aminocarbonylphenyl)-5-fluoro-N4-[(2-hydroxyethylene)-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine(R950454) A mixture of equimolar amounts of(±)-2-chloro-N4-[(2-hydroxyethylene)-3-oxo-4H-benz[1,4]oxazin-6-yl]-4-pyrimidineamineand 4-aminocarbonylaniline in MeOH was stirred in a sealed tube for 3days at 100° C. Aqueous work up gave a brown solid which was furtherpurified by column chromatography on silica gel to give(±)-N2-(4-aminocarbonylphenyl)-5-fluoro-N4-[(2-hydroxyethylene)-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine.LCMS: purity: 90.4%; MS (m/e): 437.14 (M⁻). 7.4.230N2-(4-Aminocarbonylphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950455) A mixture of equimolar amounts of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4}oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 4-aminocarbonylaniline in MeOH was stirred in a sealed tube for 3days at 100° C. Aqueous work up gave a brown solid which was furtherpurified by column chromatography on silica gel to giveN2-(4-aminocarbonylphenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 90.8%; MS (m/e): 429.14 (M⁻). 7.4.231N2-[4-(N-tert-Butoxycarbonylamino)methylenephenyl]-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950456) A mixture of equimolar amounts of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine and4-(tert-butoxycarbonylaminomethylene)aniline in MeOH was stirred in asealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togiveN2-[4-(N-tert-butoxycarbonylamino)methylenephenyl]-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 84.3%; MS (m/e): 468.26 (M⁻). 7.4.232N2-[4-(N-tert-Butoxycarbonylamino)methylenephenyl]-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950458) A mixture of equimolar amounts of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and4-(tert-butoxycarbonylaminomethylene)aniline in MeOH was stirred in asealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togiveN2-[4-(N-tert-butoxycarbonylamino)methylenephenyl]-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 91.3%; MS (m/e): 476.13 (M⁻). 7.4.233(S)-N2-[4-(N-tert-Butoxycarbonylamino)methylenephenyl]-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R950460) A mixture of equimolar amounts of(S)-2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 4-(tert-butoxycarbonylaminomethylene)aniline in MeOH was stirred ina sealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togive(S)-N2-[4-(N-tert-butoxycarbonylamino)methylenephenyl]-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.LCMS: purity: 93.5%; MS (m/e): 493.22 (M⁻). 7.4.234N2-[4-(N-tert-Butoxycarbonylamino)methylenephenyl]-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine(R950462) A mixture of equimolar amounts ofN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-2-chloro-5-fluoro-4-pyrimidineamineand 4-amino-N-tert-butoxycarbonylbenzylamine in MeOH was stirred in asealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togiveN2-[4-(N-tert-butoxycarbonylamino)methylenephenyl]-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 92.2%; MS (m/e): 519.21 (M⁻, 100). 7.4.235N2-[4-(N-tert-Butoxycarbonylaminomethylene)phenyl]-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950464) A mixture of equimolar amounts of2-chloro-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 4-(tert-butoxycarbonylaminomethylene)aniline in MeOH was stirred ina sealed tube for 3 days at 100° C. Aqueous work up gave a brown solidwhich was further purified by column chromatography on silica gel togiveN2-[4-(N-tert-butoxycarbonylaminomethylene)phenyl]-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 89.2%; MS (m/e): 515.18 (M⁻). 7.4.236N2-(4-Aminomethylenephenyl)-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R950457)N2-[4-(N-tert-Butoxycarbonylamino)methylenephenyl]-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to giveN2-(4-aminomethylenephenyl)-N4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 92.2%; MS (m/e): 368.20 (M⁻). 7.4.237N2-(4-Aminomethylenephenyl)-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R950459)N2-[4-(N-tert-Butoxycarbonylamino)methylenephenyl]-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to giveN2-(4-aminomethylenephenyl)-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 94.0%; MS (m/e): 376.06 (M⁻). 7.4.238(S)-N2-(4-Aminomethylenephenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R950461)(S)-N2-[4-(N-tert-Butoxycarbonylamino)methylenephenyl]-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to give(S)-N2-(4-aminomethylenephenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.LCMS: purity: 94.7%; MS (m/e): 393.15 (M⁻). 7.4.239N2-(4-Aminomethylenphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine(R950463)N4-(4,4-Dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-[4-(N-tert-butoxycarbonylaminomethylen)phenyl]-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to giveN2-(4-aminomethylenphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 92.3%; MS (m/e): 419.49 (M⁻). 7.4.240N2-(4-Aminomethylenephenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R950465)N2-[4-(N-tert-Butoxycarbonylaminomethylene)phenyl]-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminewas suspended in dichloromethane and treated with trifluoroacetic acid.The mixture was stirred for 30 minutes at 22° C. and concentrated todryness under reduced pressure. The residue was neutralized with sodiumbicarbonate and crystallized from MeOH-water to giveN2-(4-aminomethylenephenyl)-N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 93.9%; MS (m/e): 415.3 (M⁻). 7.4.241N4-(3,5-Dimethoxyphenyl)-N2-(3-N,N-diethylaminopropyl)-5-fluoro-2,4-pyrimidinediamine(R950469) A mixture of equimolar amounts of2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine and3-N,N-diethylaminopropylamine in MeOH was stirred in a sealed tube for 3days at 100° C. Aqueous work up gave a brown solid which was furtherpurified by column chromatography on silica gel to giveN4-(3,5-dimethoxyphenyl)-N2-(3-N,N-diethylaminopropyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 94.3%; MS (m/e): 378.33 (MH⁺). 7.4.242N4-(3,4-Dichlorophenyl)-N2-(3-N,N-diethylaminopropyl)-5-fluoro-2,4-pyrimidinediamine(R950470) A mixture of equimolar amounts of2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and3-N,N-diethylaminopropylamine in MeOH was stirred in a sealed tube for 3days at 100° C. Aqueous work up gave a brown solid which was furtherpurified by column chromatography on silica gel to giveN4-(3,4-dichlorophenyl)-N2-(3-N,N-diethylaminopropyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 100%; MS (m/e): 386.18 (MH⁺). 7.4.243(S)-N2-(3-N,N-Diethylaminopropyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R950471) A mixture of equimolar amounts of(S)-2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidineamineand 3-N,N-diethylaminopropylamine in MeOH was stirred in a sealed tubefor 3 days at 100° C. Aqueous work up gave a brown solid which wasfurther purified by column chromatography on silica gel to give(S)-N2-(3-N,N-diethylaminopropyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.LCMS: purity: 86.3%; MS (m/e): 403.34 (MH⁺). 7.4.244N4-(4,4-Dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-N2-(3-N,N-diethylaminopropyl)-5-fluoro-2,4-pyrimidinediamine(R950472) A mixture of equimolar amounts ofN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-2-chloro-5-fluoro-4-pyrimidineamineand 3-N,N-diethylaminopropylamine in MeOH was stirred in a sealed tubefor 3 days at 100° C. Aqueous work up gave a brown solid which wasfurther purified by column chromatography on silica gel to giveN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-N2-(3-N,N-diethylaminopropyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 95.9%; MS (m/e): 429.51 (MH⁺). 7.4.245(±)-5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-(N-p-toluenesulfonyl)amino-1-benzopyran-6-yl)-2,4-pyrimidinediamine(R950493) A solution of(±)-N4-(4-amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediaminein THF:DMF was treated with p-tolunesulfonyl chloride and triethylamine.The mixture was stirred for 1 hour at 0° C. and diluted with hexane. Thereaction mixture was filtered, and the remaining solids were dried andsubjected to column chromatography to(±)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-(N-p-toluenesulfonyl)amino-1-benzopyran-6-yl)-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.24 (s, 1H), 9.00 (s, 1H), 8.01(d, 1H, J=2.4 Hz), 8.16 (d, 1H, J=7.8 Hz), 7.63-8.05 (m, 4H), 7.21-7.37(m, 5H), 7.08 (t, 1H, J=7.8 Hz), 6.69 (d, 1H, J=8.4 Hz), 6.46 (d, 1H,J=6.9 Hz), 4.40 (m, 1H0, 4.29 (s, 1H), 4.10 (m, 2H), 3.33 (s, 3H), 2.64(s, 3H), 1.88-2.08 (m, 2H); LCMS: purity: 94.0%; MS (m/e): 591.16 (M⁻).7.4.246(±)-2-Chloro-5-fluoro-N4-[4-(N-methansulfonyl)amino-1-benzopyran-6-yl)-4-pyrimidineamineA solution of (±)-4-amino-6-nitro-1-benzopyran in DMF was treated withtriethylamine and methanesulfonyl chloride. The mixture was stirred for30 minutes at 0° C. and diluted with dichloromethane. Aqueous workupgave the expected (±)-4-(N-methanesulfonyl)amino-6-nitro-1-benzopyran asa yellow solid. This solid and Pd/C (10%) were suspended in MeOH and themixture was hydrogenated at 22° C. for 3 hours (40 psi). The mixture wasfiltered and concentrated to dryness to give(±)-4-(N-methanesulfonyl)amino-6-amino-1-benzopyran as a brown oil,which was reacted with 2,4-dichloro-5-fluoropyrimidine in MeOH for 2hours at 70° C. The mixture was diluted with water and the resultingprecipitate was filtered to give(±)-2-chloro-5-fluoro-N4-[4-(N-methansulfonyl)amino-1-benzopyran-6-yl)-4-pyrimidineamineas a pale yellow solid. LCMS: purity: 91.3%; MS (m/e): 373.02 (MH⁺).7.4.247 (±)-5-FluoroN4-[4-(N-methanesulfonyl)amino-1-benzopyran-6-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950494) A solution of equimolar amount of(±)-2-chloro-5-fluoro-N4-[4-(N-methansulfonyl)amino-1-benzopyran-6-yl)-4-pyrimidineamineand 3-(N-methylamino)carbonylmethyleneoxyaniline were dissolved in MeOHand heated in a sealed tube at 110° C. for 24 hours. Aqueous work upgave (±)-5-fluoroN4-[4-(N-methanesulfonyl)amino-1-benzopyran-6-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆): δ9.33 (s, 1H), 8.91 (s, 1H), 8.03(d, 1H, J=2.4 Hz), 7.94 (m, 1H), 7.78 (m, 1H), 7.66 (d, 1H, J=8.4 Hz),7.22-7.62 (m, 3H), 7.09 (t, 1H, J=8.1 Hz), 6.72 (d, 1H, J=8.7 Hz), 6.45(m 1H), 4.56 (m, 1H), 4.32 (s, 2H), 4.17 (m, 2H), 3.29 (s, 3H), 2.65 (s,3H), 1.75-2.16 (m, 2H); LCMS: purity: 95.6%; MS (m/e): 515.05 (M⁻).7.4.248(±)-N4-[4-N-(N,N-Dimethylaminomethylencarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950416) A solution of(±)-N4-(4-amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand N,N-diaminoglycine in DMF was treated with PyBroP followed bydiisopropylethylamine. The mixture was stirred for 30 minutes at 22° C.and diluted with hexane. The mixture was filtered, and the remainingsolid was dried and subjected to column chromatography to give(±)-N4-[4-N-(N,N-dimethylaminomethylencarbonyl)amino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. LCMS: purity: 95.6%; MS (m/e): 522.26 (M⁻). 7.4.249(±)-N4-[4-N-(N,N-Dimethylaminomethylencarbonyl)-N-methylamino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R950419) A solution of(±)-N4-(4-amino-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineand N,N-diaminoglycine in DMF was treated with PyBroP followed bydiisopropylethylamine. The mixture was stirred for 30 minutes at 22° C.and diluted with hexane. The mixture was filtered, and the remainingsolids were dried and subjected to column chromatography to give(±)-N4-[4-N-(N,N-dimethylaminomethylencarbonyl)-N-methylamino-1-benzopyran-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineas a white solid. ¹H NMR (DMSO-d₆ , 2 rotamers): δ9.28 (s, 1H), 9.19 (s,1H), 9.03 (s, 1H), 8.92 (s, 1H), 7.01-8.04 (14H), 6.74 (d, 2H, J=9.0Hz), 6.45 (m, 2H), 5.80 (m, 1H), 5.51 (m, 1H), 4.08-4.31 (m, 8H),3.15-3.39 (m, 4H), 3.32 (s, 6H), 3.30 (s, 3H), 3.27 (m, 3H), 2.64 (s,6H), 1.90-2.12 (m, 4H); LCMS: purity: 94.3%; MS (m/e): 536.30 (M⁻).7.4.250N4-Cyclopropyl-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine(R945356) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) and cyclopropylamine(50 mg) were reacted to yield2-chloro-N4-cyclopropyl-5-fluoro-4-pyrimidineamine. In a manner similarto the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-morpholinoaniline (150 mg) and2-chloro-N4-cyclopropyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN4-cyclopropyl-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.63 (m, 2H), 0.88 (m, 2H), 2.82 (m, 1H), 3.10 (t,J=4.8 Hz, 4H), 3.86 (t, J=4.8 Hz, 4H), 5.16 (s, 1H), 6.89 (d, J=9.0 Hz,2H), 6.94 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.74 (d, J=3.6 Hz, 1H); ¹⁹FNMR (282 MHz, CDCl₃): δ- 169.88; LCMS: ret. time: 7.13 min.; purity:91.61%; MS (m/e): 330.26 (MH⁺). 7.4.251N2-Cyclopropyl-5-fluoro-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine(R945357) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine (300 mg, 1.8 mmol) and4-morpholinoaniline (200 mg) were reacted at room temperature to yield2-chloro-5-fluoro-N4-(4-morpholinophenyl)-4-pyrimidineamine. In a mannersimilar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,cyclopropylamine(200 mg) and2-chloro-5-fluoro-N4-(4-morpholinophenyl)-4-pyrimidineamine (100 mg)were reacted to giveN2-cyclopropyl-5-fluoro-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.52 (m, 2H), 0.77 (m, 2H), 2.69 (m, 1H), 3.12 (t,J=4.8 Hz, 4H), 3.85 (t, J=4.8 Hz, 4H), 5.16 (s, 1H), 6.66 (s, 1H), 6.89(d, J=9.0 Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 7.84 (d, J=3.6 Hz, 1H); ¹⁹FNMR (282 MHz, CDCl₃): δ- 170.72; LCMS: ret. time: 6.77 min.; purity:88.87%; MS (m/e): 330.22 (MH⁺). 7.4.252N2-Cyclobutyl-5-fluoro-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine(R945358) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,cyclobutylamine (200 mg) and2-chloro-5-fluoro-N4-(4-morpholinophenyl)-4-pyrimidineamine (100 mg)were reacted to giveN2-cyclobutyl-5-fluoro-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine. ¹HNMR (CDCl₃): δ1.68-1.90 (m, 4H), 2.34-2.43 (m, 2H), 3.14 (t, J=4.8 Hz,4H), 3.87 (t, J=4.8 Hz, 4H), 4.32 (m, J=7.8 Hz, 1H), 5.18 (s, 1H), 6.61(s, 1H), 6.92 (d, J=9.0 Hz, 2H), 7.53 (d, J=9.0 Hz, 2H), 7.78 (d, J=3.6Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 171.07; LCMS: ret. time: 8.05min.; purity: 79.69%; MS (m/e): 344.22 (MH⁺). 7.4.253N2-[3-(N-Cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine(R945360) 3-(Methoxycarbonylmethyleneoxy)nitrobenzene (2 g),cyclopropylamine (1 g) and triethylamine (1 mL) were dissolved inmethanol (10 mL) and heated in a sealed tube at 100° C. overnight. Thereaction solution was then diluted with 1N HCl aq. solution (80 mL). Thewhite precipitation was collected by filtration and washed with water,dried to give 3-(N-cyclopropylaminocarbonylmethyleneoxy)nitrobenzene. ¹HNMR (CDCl₃): δ0.60 (m, 2H), 0.85 (m, 2H), 2.80 (m, J=3.6 Hz, 1H), 4.53(s, 2H), 6.61 (br, 1H, NH), 7.23 (ddd, J=0.6 and 2.7 and 8.4 Hz, 1H),7.49 (t, J=8.4 Hz, 1H), 7.77 (t, J=2.4 Hz, 1H), 7.90 (ddd, J=0.9 and 2.1and 8.1 Hz, 1H). 3-(N-Cyclopropylaminocarbonylmethyleneoxy)nitrobenzenewas reduced under hydrogenolysis conditions using 10% Pd-C in methanolat 40 psi for 2 h. The catalyst was filtered off. The filtrate wasevaporated to give 3-(N-cyclopropylaminocarbonylmethyleneoxy)aniline. ¹HNMR (CDCl₃): δ0.38 (m, 2H), 0.58 (m, 2H), 2.56 (m, J=3.6 Hz, 1H), 4.19(s, 2H), 6.08 (m, 2H), 6.15 (d, J=8.1 Hz, 1H), 6.83 (t, J=8.1 Hz, 1H),7.09 (br, 1H, NH). In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(N-cyclopropylaminocarbonylmethyleneoxy)aniline (200 mg) and2-chloro-5-fluoro-N4-(4-morpholinophenyl)-4-pyrimidineamine (100 mg)were reacted to giveN2-[3-(N-cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.55 (m, 2H), 0.81 (m, 2H), 2.77 (m, J=3.6 Hz, 1H),3.14 (t, J=4.8 Hz, 4H), 3.87 (t, J=4.8 Hz, 4H), 4.40 (s, 2H), 6.52 (ddd,J=0.9 and 2.4 and 8.1 Hz, 1H), 6.61 (br, 1H, NH), 6.79 (d, J=2.4 Hz,1H), 6.92 (d, J=9.0 Hz, 2H), 7.02 (dt, J=0.9 and 8.1 Hz, 1H), 7.11 (br,1H, NH), 7.18 (t, J=8.4 Hz, 1H), 7.40 (t, J=2.4 Hz, 1H), 7.48 (d, J=9.3Hz, 2H), 7.92 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 166.86;LCMS: ret. time: 8.57 min.; purity: 88.55%; MS (m/e): 479.31 (MH⁺).7.4.2545-Fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine(R945361) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-[(4-morpholinophenyl)aminocarbonylmethyleneoxy]aniline (200 mg) and2-chloro-5-fluoro-N4-(4-morpholinophenyl)-4-pyrimidineamine (100 mg)were reacted in methanol to give5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ3.15 (t, J=4.8 Hz, 4H), 3.80 (s, 3H), 3.88 (t, J=4.8Hz, 4H), 4.55 (s, 2H), 6.55 (ddd, J=0.9 and 2.7 and 8.1 Hz, 1H), 6.76(br, 1H, NH), 6.94 (d, J=9.0 Hz, 2H), 7.06 (ddd, J=0.9 and 2.1 and 8.4Hz, 1H), 7.17 (t, J=8.4 Hz, 1H), 7.20 (br, 1H, NH), 7.33 (t, J=2.1 Hz,1H), 7.49 (d, J=9.0 Hz, 2H), 7.90 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz,CDCl₃): δ- 167.19; LCMS: ret. time: 9.32 min.; purity: 97.10%; MS (m/e):454.27 (MH⁺). 7.4.255N2-[3-(N-Cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine(R945362) In a manner similar to the preparation of3-(N-cyclopropylaminocarbonylmethyleneoxy)nitrobenzene,3-(methoxycarbonylmethyleneoxy)nitrobenzene (2 g) and cyclobutylamine (1g) were reacted to give3-(N-cyclobutylaminocarbonylmethyleneoxy)nitrobenzene. ¹H NMR (CDCl₃):δ1.69-1.80 (m, 2H), 1.88-2.02 (m, 2H), 2.34-2.44 (m, 2H), 4.50 (m, J=8.7Hz, 1H), 4.52 (s, 2H), 6.62 (br, 1H, NH), 7.26 (ddd, J=0.9 and 3.6 and9.0 Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 7.80 (t, J=2.4 Hz, 1H), 7.91 (ddd,J=0.9 and 2.1 and 8.4 Hz, 1H).3-(N-Cyclobutylaminocarbonylmethyleneoxy)nitrobenzene was reduced underhydrogenolysis conditions using 10% Pd-C in methanol at 40 psi for 2 h.The catalyst was filtered off. The filtrate was evaporated to give3-(N-cyclobutylaminocarbonylmethyleneoxy)aniline. ¹H NMR (CDCl₃):δ1.60-1.70 (m, 2H), 1.80-1.93 (m, 2H), 2.62 (m, 2H), 4.31 (s, 2H), 4.36(m, J=8.4 Hz, 1H), 6.20 (s, 1H), 6.23 (d, J=8.4 Hz, 1H), 6.28 (d, J=8.1Hz, 1H), 6.85 (br, 1H, NH), 6.99 (t, J=8.1 Hz, 1H). In a manner similarto the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(N-cyclobutylaminocarbonylmethyleneoxy)aniline (200 mg) and2-chloro-5-fluoro-N4-(4-morpholinophenyl)-4-pyrimidineamine (100 mg)were reacted to giveN2-[3-(N-cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.65-1.76 (m, 2H), 1.84-1.97 (m, 2H), 2.29-2.39 (m,2H), 3.12 (t, J=4.8 Hz, 4H), 3.86 (t, J=4.8 Hz, 4H), 4.37 (s, 2H), 4.46(q, J=8.1 Hz, 1H), 6.54 (ddd, J=0.9 and 2.4 and 8.4 Hz, 1H), 6.68 (d,J=8.1 Hz, 1H), 6.85 (dd, J=3.0 and 5.4 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H),7.04 (ddd, J=0.9 and 2.4 and 7.8 Hz, 1H), 7.16 (br, 1H, NH), 7.17 (t,J=8.1 Hz, 1H), 7.40 (t, J=2.1 Hz, 1H), 7.48 (d, J=9.0 Hz, 2H), 7.92 (d,J=3.3 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 167.01; LCMS: ret. time:9.54 min.; purity: 88.80%; MS (m/e): 493.34 (MH⁺). 7.4.256N4-Cyclopropyl-N2-[3-(N-cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R945363) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(N-cyclopropylaminocarbonylmethyleneoxy)aniline (200 mg) and2-chloro-N4-cyclopropyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN4-cyclopropyl-N2-[3-(N-cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ0.55 (m, 2H), 0.72-0.79 (m, 4H), 0.89-0.96 (m, 2H),2.72 (m, J=3.6 Hz, 1H), 3.03 (m, J=3.6 Hz, 1H), 4.50 (s, 2H), 6.82 (ddd,J=0.9 and 2.1 and 8.4 Hz, 1H), 7.17 (ddd, J=1.8 and 7.8 Hz, 1H), 7.33(m, 2H), 7.80 (d, J=5.7 Hz, 1H), 8.20 (br, 1H, NH); ¹⁹F NMR (282 MHz,CD₃OD): δ- 164.97; LCMS: ret. time: 7.47 min.; purity: 97.25%; MS (m/e):358.23 (MH⁺). 7.4.257N2-[3-(N-Cyclobutylamino)carbonylmethyleneoxyphenyl]-N4-cyclopropyl-5-fluoro-2,4-pyrimidinediamine(R945364) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(N-cyclobutylaminocarbonylmethyleneoxy)aniline (200 mg) and2-chloro-N4-cyclopropyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN4-cyclopropyl-N2-[3-(N-cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CD₃OD): δ0.72 (m, 2H), 0.87-0.94 (m, 2H), 1.68-1.79 (m, 2H),1.97-2.11 (m, 2H), 2.23-2.33 (m, 2H), 2.99 (m, J=3.6 Hz, 1H), 4.39 (m,J=8.1 Hz, 1H), 4.48 (s, 2H), 6.77 (ddd, J=0.9 and 2.4 and 7.8 Hz, 1H),7.18 (ddd, J=0.9 and 1.8 and 8.1 Hz, 1H), 7.29 (t, J=8.1 Hz, 1H), 7.43(d, J=2.1 Hz, 1H), 7.78 (d, J=4.8 Hz, 1H), 8.19 (br, 1H, NH); ¹⁹F NMR(282 MHz, CD₃OD): δ- 166.31; LCMS: ret. time: 8.72 min.; purity: 97.16%;MS (m/e): 372.24 (MH⁺). 7.4.258N4-Cyclopropyl-5-fluoro-N2-[3-(4-morpholinophenyl)aminocarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945365) 3-(Methoxycarbonylmethyleneoxy)nitrobenzene (2 g),4-morpholinoaniline ( 1 g) and triethylamine (1 mL) were dissolved inmethanol (10 mL) and heated at 100° C. for 3 days. The reaction solutionwas then diluted with 1N HCl aq. solution (80 mL) and ethyl acetate (60mL). The white precipitation was collected by filtration and washed withwater, dried to give3-[(4-morpholinophenyl)aminocarbonylmethyleneoxy]nitrobenzene. ¹H NMR(DMSO-d₆): δ3.24 (s, 4H), 3.85 (s, 4H), 4.85 (s, 2H), 7.27 (m, 2H), 7.48(dd, J=2.4 and 8.4 Hz, 1H), 7.57-7.63 (m, 3H), 7.80-7.86 (m, 2H), 10.22(br, 1H, NH).3-[(4-Morpholinophenyl)aminocarbonylmethyleneoxy]nitrobenzene wasreduced under hydrogenolysis conditions using 10% Pd-C in methanol at 40psi for 2 h. The catalyst was filtered off. The filtrate was evaporatedto give 3-[(4-morpholinophenyl)aminocarbonylmethyleneoxy]aniline. ¹H NMR(CDCl₃): δ3.12 (t, J=4.8 Hz, 4H), 3.86 (t, J=4.8 Hz, 4H), 4.54 (s, 2H),6.31-6.38 (m, 3H), 6.90 (d, J=9.0 Hz, 2H), 7.09 (t, J=7.8 Hz, 1H), 7.45(d, J=9.0 Hz, 2H), 8.19 (br, 1H, NH). In a manner similar to thepreparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-[(4-morpholinophenyl)aminocarbonylmethyleneoxy]aniline (200 mg) and2-chloro-N4-cyclopropyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN4-cyclopropyl-5-fluoro-N2-[3-(4-morpholinophenyl)aminocarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.64-0.69 (m, 2H), 0.88-0.96 (m, 2H), 2.87 (m, J=3.3Hz, 1H), 3.12 (t, J=4.8 Hz, 4H), 3.86 (t, J=4.8 Hz, 4H), 4.61 (s, 2H),6.60 (ddd, J=0.9 and 2.4 and 8.1 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 7.11(dd, J=1.8 and 8.1 Hz, 1H), 7.23 (t, J=8.4 Hz, 1H), 7.31 (s, 1H), 7.46(d, J=9.0 Hz, 2H), 7.75 (t, J=2.7 Hz, 1H), 7.79 (d, J=3.3 Hz, 1H), 8.16(br, 1H, NH); ¹⁹F NMR (282 MHz, CDCl₃): δ- 168.10; LCMS: ret. time: 9.03min.; purity: 99.97%; MS (m/e): 479 (MH⁺). 7.4.259N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945366) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(methylaminocarbonylmethyleneoxy)aniline (200 mg) and2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine(100 mg) were reacted to giveN4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ2.17 (s, 3H), 2.62 (d, J=4.8 Hz, 3H), 4.35 (s, 2H),6.56 (d, J=8.4 Hz, 1H), 7.14 (m, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.41 (t,J=3.3 Hz, 1H), 7.54 (t, J=3.3 Hz, 1H), 7.94 (br, 1H), 8.12 (d, J=4.2 Hz,1H), 8.98 (br, 1H), 9.55 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ-167.17; LCMS: ret. time: 8.56 min.; purity: 95.27%; MS (m/e): 432.15(MH⁺). 7.4.2605-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine(R945367) In a manner similar to the preparation of3-(N-cyclopropylaminocarbonylmethyleneoxy)nitrobenzene,5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine(30 mg) and methylamine (30 mg) were reacted to give5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-N4-(4-morpholinophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ2.63 (d, J=4.5 Hz, 3H), 3.04 (t, J=4.8 Hz, 4H), 3.72(t, J=4.8 Hz, 4H), 4.32 (s, 2H), 6.46 (dd, J=7.8 Hz, 1H), 6.90 (d, J=9.0Hz, 2H), 7.08 (t, J=8.1 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.37 (s, 1H),7.60 (dd, J=3.3 and 8.7 Hz, 2H), 7.94 (br, 1H), 8.02 (d, J=3.9 Hz, 1H),9.12 (br, 1H), 9.15 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 167.17;LCMS: ret. time: 7.88 min.; purity: 99.47%; MS (m/e): 453.21 (MH⁺).7.4.2615-Fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945368) 1-(4-Nitrophenyl)piperazine (1 g), methyl chloroformate (1 mL)and triethylamine (1 mL) were reacted at room temperature indichloromethane (10 mL) overnight. After extraction between ethylacetate and water, the organic layer was evaporated and recrystallizedfrom dichloromethane and hexanes to give4-(4-methoxycarbonylpiperazino)nitrobenzene as yellow solid. It wasreduced under hydrogenolysis conditions using 10% Pd-C in methanol at 60psi for 1 h. The catalyst was filtered off. The filtrate was evaporatedto give 4-(4-methoxycarbonylpiperazino)aniline. ¹H NMR (CDCl₃): δ2.94(t, J=5.1 Hz, 4H), 3.59 (t, J=5.1 Hz, 4H), 3.70 (s, 3H), 6.62 (d, J=8.7Hz, 2H), 6.78 (d, J=9.0 Hz, 2H). In a manner similar to the preparationof 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine (300 mg, 1.8 mmol) and4-(4-methoxycarbonylpiperazino)aniline (300 mg) were reacted to yield2-chloro-5-fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-4-pyrimidineamine.In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(methylaminocarbonylmethyleneoxy)aniline (150 mg) and2-chloro-5-fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-4-pyrimidineamine(100 mg) were reacted to give5-fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ2.63 (d, J=4.8 Hz, 3H), 3.04 (t, J=5.1Hz, 4H), 3.50(t, J=5.1 Hz, 4H), 3.61 (s, 3H), 4.32 (s, 2H), 6.46 (dd, J=2.1 and 7.8Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 7.08 (t, J=5.1 Hz, 1H), 7.24 (dd, J=0.9and 8.4 Hz, 1H), 7.38 (t, J=2.1 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.95(d, J=3.9 Hz, 1H), 8.02 (d, J=3.6 Hz, 1H), 9.13 (s, 1H, NH), 9.17 (s,1H, NH); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 164.93; LCMS: ret. time: 8.50min.; purity: 94.49%; MS (m/e): 510.28 (MH⁺). 7.4.262N2-[4-(N-Acetyl-N-methylamino)phenyl]-N4-cyclopropyl-5-fluoro-2,4-pyrimidinediamine(R945369) In a manner similar to the preparation of4-(4-methoxycarbonylpiperazino)nitrobenzene, N-methyl-4-nitroaniline (1g) and acetyl chloride (1 mL) were reacted to yieldN-acetyl-N-methyl-4-nitroaniline. ¹H NMR (CDCl₃): δ2.03 (s, 3H), 3.35(s, 3H), 7.39 (d, J=9.0 Hz, 2H), 8.28 (d, J=9.0 Hz, 2H).N-Acetyl-N-methyl-4-nitroaniline was reduced under hydrogenolysisconditions using 10% Pd-C in methanol at 60 psi for 1 h. The catalystwas filtered off. The filtrate was evaporated to give4-(N-acetyl-N-methylamino)aniline. ¹H NMR (CDCl₃): δ1.80 (s, 3H), 3.14(s, 3H), 6.63 (d, J=8.1 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H). In a mannersimilar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(N-acetyl-N-methylamino)aniline (200 mg) and2-chloro-N4-cyclopropyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN2-[4-(N-acetyl-N-methylamino)phenyl]-N4-cyclopropyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.67 (m, 2H), 0.83-0.97 (m, 2H), 1.88 (s, 3H), 2.85 (m,J=3.3 Hz, 1H), 3.24 (s, 3H), 5.31 (br, 1H), 7.10 (d, J=8.7 Hz, 2H), 7.36(br, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.78 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282MHz, CDCl₃): δ- 168.13; LCMS: ret. time: 6.65 min.; purity: 100%; MS(m/e): 316.22 (MH⁺). 7.4.263N2-[4-(4-Acetylpiperazino)phenyl]-N4-cyclopropyl-5-fluoro-2,4-pyrimidinediamine(R945370) In a manner similar to the preparation of4-(4-methoxycarbonylpiperazino)nitrobenzene, 1-(4-nitrophenyl)piperazine(1 g) and acetyl chloride (1 mL) were reacted to yield4-(4-acetylpiperazino)nitrobenzene. ¹H NMR (CDCl₃): δ2.16 (s, 3H), 3.46(br, 4H), 3.68 (br, 2H), 3.80 (br, 2H), 6.84 (d, J=9.6 Hz, 2H), 8.15 (d,J=9.6 Hz, 2H). 4-(4-Acetylpiperazino)nitrobenzene was reduced underhydrogenolysis conditions using 10% Pd-C in methanol at 60 psi for 1 h.The catalyst was filtered off. The filtrate was evaporated to give4-(4-acetylpiperazino)aniline. ¹H NMR (CDCl₃): δ2.10 (s, 3H), 2.97 (p,J=4.8 Hz, 4H), 3.58 (t, J=4.8 Hz, 2H), 3.72 (t, J=5.1 Hz, 2H), 6.64 (d,J=8.7 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H). In a manner similar to thepreparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-acetylpiperazino)aniline (200 mg) and2-chloro-N4-cyclopropyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN2-[4-(4-acetylpiperazino)phenyl]-N4-cyclopropyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.66 (m, 2H), 0.90 (m, 2H), 2.14 (s, 3H), 2.84 (m,J=3.3 Hz, 1H), 3.10 (p, J=5.1 Hz, 4H), 3.62 (t, J=5.1 Hz, 2H), 3.77 (t,J=5.1 Hz, 2H), 5.33 (br, 1H), 6.90 (d, J=9.0 Hz, 2H), 7.43 (br, 1H),7.57 (d, J=9.0 Hz, 2H), 7.71 (d, J=3.6 Hz, 1H); ¹⁹F NMR (282 MHz,CDCl₃): δ- 168.95; LCMS: ret. time: 6.79 min.; purity: 93.14%; MS (m/e):371.50 (MH⁺). 7.4.264N4-Cyclopropyl-5-fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine(R945371) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-methoxycarbonylpiperazino)aniline (200 mg) and2-chloro-N4-cyclopropyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN4-cyclopropyl-5-fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.65 (m, 2H), 0.88 (m, 2H), 2.84 (m, J=3.3 Hz, 1H),3.07 (t, J=4.8 Hz, 4H), 3.63 (t, J=5.1 Hz, 4H), 3.73 (s, 3H), 5.29 (br,1H), 6.90 (d, J=9.0 Hz, 2H), 7.38 (br, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.71(d, J=3.6 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 169.13; LCMS: ret. time:7.86 min.; purity: 91.63%; MS (m/e): 387.20 (MH⁺). 7.4.265N4-Cyclopropyl-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945372) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(methylaminocarbonylmethyleneoxy)aniline (200 mg) and2-chloro-N4-cyclopropyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN4-cyclopropyl-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.66 (m, 2H), 0.91 (m, 2H), 2.87 (m, 1H), 2.90 (d,J=5.1 Hz, 3H), 4.50 (s, 2H), 5.32 (br, 1H), 6.52 (ddd, J=0.9 and 2.4 and7.8 Hz, 1H), 6.60 (br, 1H), 7.13 (ddd, J=1.2 and 8.1 Hz, 1H), 7.20 (t,J=8.1 Hz, 1H), 7.31 (br, 1H), 7.61 (t, J=2.1 Hz, 1H), 7.80 (d, J=3.6 Hz,1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 168.24; LCMS: ret. time: 6.78 min.;purity: 89.65%; MS (m/e): 332.19 (MH⁺). 7.4.266N2-Cyclopropyl-5-fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine(R945373) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,cyclopropylamine (150 mg) and2-chloro-5-fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-4-pyrimidineamine(100 mg) were reacted to giveN2-cyclopropyl-5-fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.60 (m, 2H), 0.81 (m, 2H), 2.72 (m, J=3.3 Hz, 1H),3.13 (t, J=5.1 Hz, 4H), 3.64 (t, J=5.1 Hz, 4H), 3.73 (s, 3H), 6.92 (d,J=9.0 Hz, 2H), 7.63 (d, J=9.0 Hz, 2H), 7.76 (d, J=3.0 Hz, 1H); ¹⁹F NMR(282 MHz, CDCl₃): δ- 168.70; LCMS: ret. time: 7.59 min.; purity: 92.07%;MS (m/e): 387.27 (MH⁺). 7.4.267N2-Cyclobutyl-5-fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine(R945374) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,cyclobutylamine (150 mg) and2-chloro-5-fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-4-pyrimidineamine(100 mg) were reacted to giveN2-cyclobutyl-5-fluoro-N4-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.68-1.78 (m, 2H), 1.82-1.92 (m, 2H), 2.33-2.43 (m,2H), 3.12 (t, J=5.1 Hz, 4H), 3.64 (t, J=5.1 Hz, 4H), 3.74 (s, 3H), 4.31(m, J=7.8 Hz, 1H), 5.42 (br, 1H), 6.69 (br, 1H), 6.93 (d, J=9.3 Hz, 2H),7.53 (d, J=9.0 Hz, 2H), 7.76 (d, J=3.6 Hz, 1H); ¹⁹F NMR (282 MHz,CDCl₃): δ- 170.64; LCMS: ret. time: 8.34 min.; purity: 82.53%; MS (m/e):401.28 (MH⁺). 7.4.268N4-[4-(N-Acetyl-N-methylamino)phenyl]-N2-cyclopropyl-5-fluoro-2,4-pyrimidinediamine(R945375) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine (300 mg, 1.8 mmol) and4-(N-acetyl-N-methylamino)aniline (300 mg) were reacted to yieldN4-[4-(N-acetyl-N-methylamino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine.In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,cyclopropylamine (150 mg) andN4-[4-(N-acetyl-N-methylamino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(100 mg) were reacted to giveN4-[4-(N-acetyl-N-methylamino)phenyl]-N2-cyclopropyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.66 (m, 2H), 0.85 (m, 2H), 1.90 (s, 3H), 2.74 (m, 1H),3.27 (s, 3H), 7.22 (d, 2H), 7.84 (d, 3H); LCMS: ret. time: 5.91 min.;purity: 79.74%; MS (m/e): 316.23 (MH⁺). 7.4.269N2,N4-Bis(cyclopropyl)-5-fluoro-2,4-pyrimidinediamine (R945376) Duringthe preparation ofN4-[4-(N-acetyl-N-methylamino)phenyl]-N2-cyclopropyl-5-fluoro-2,4-pyrimidinediamine,the formation of N2,N4-bis(cyclopropyl)-5-fluoro-2,4-pyrimidinediamineas a by product was observed. ¹H NMR (CDCl₃): δ0.49-0.59 (m, 4H),0.73-0.84 (m, 4H), 2.67-2.79 (m, 2H), 5.04 (br, 1H), 5.14 (br, 1H), 7.73(d, J=3.6 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 171.76; LCMS: ret. time:2.63 min.; purity: 96.91%; MS (m/e): 209.16 (MH⁺). 7.4.270N4-[4-(N-Acetyl-N-methylamino)phenyl]-5-fluoro-N2-[3-N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine(R945377) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(N-methylamino)carbonylmethyleneoxyaniline (150 mg) andN4-[4-(N-acetyl-N-methylamino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(100 mg) were reacted to giveN4-[4-(N-acetyl-N-methylamino)phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.89 (s, 3H), 2.89 (d, J=5.1 Hz, 3H), 3.26 (s, 3H),4.47 (s, 2H), 6.59 (dd, J=2.4 and 8.1 Hz, 1H), 7.12-7.24 (m, 4H), 7.30(br, 1H), 7.35 (t, J=2.1 Hz, 1H), 7.70 (d, J=8.4 Hz, 2H), 8.01 (d, J=3.0Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 165.91; LCMS: ret. time: 7.94min.; purity: 89.78%; MS (m/e): 439.50 (MH⁺). 7.4.271N2,N4-Bis(3-methylaminocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945378) During the synthesis ofN4-[4-(N-acetyl-N-methylamino)phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine,the formation ofN2,N4-bis(3-methylaminocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamineas a by product was observed. ¹H NMR (CDCl₃): δ2.87 (d, J=4.8 Hz, 3H),2.90 (d, J=4.8 Hz, 3H), 4.46 (s, 2H), 4.54 (s, 2H), 6.53 (ddd, J=0.9 and2.4 and 7.8 Hz, 2H), 6.69 (ddd, J=0.9 and 2.7 and 8.1 Hz, 2H), 6.82 (dd,J=1.2 and 7.8 Hz, 1H), 6.92 (d, J=3.0 Hz, 1H), 7.19-7.30 (m, 3H), 7.65(t, J=2.1 Hz, 1H), 8.00 (d, J=3.3 Hz, 1H), 8.04 (br, 1H), 8.12 (t, J=2.1Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 167.11; LCMS: ret. time: 7.93min.; purity: 96.85%; MS (m/e): 455.50 (MH⁺). 7.4.272N4-[4-(N-Acetyl-N-methylamino)phenyl]-N2-cyclobutyl-5-fluoro-2,4-pyrimidinediamine(R945379) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,cyclobutylamine (150 mg) andN4-[4-(N-acetyl-N-methylamino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(100 mg) were reacted to giveN4-[4-(N-acetyl-N-methylamino)phenyl]-N2-cyclobuyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.70-1.97 (m, 4H), 1.89 (s, 3H), 2.36-2.45 (m, 2H),3.26 (s, 3H), 4.33 (m, J=7.8 Hz, 1H), 5.13 (d, J=7.2 Hz, 1H), 6.87 (br,1H), 7.16 (d, J=8.7 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 7.86 (d, J=3.6 Hz,1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 170.61; LCMS: ret. time: 7.03 min.;purity: 93.04%; MS (m/e): 330.16 (MH⁺). 7.4.273N2,N4-Bis(cyclobutyl)-5-fluoro-2,4-pyrimidinediamine (R945380) Duringthe preparation ofN4-[4-(N-acetyl-N-methylamino)phenyl]-N2-cyclobuyl-5-fluoro-2,4-pyrimidinediamine,the formation of N2,N4-bis(cyclobutyl)-5-fluoro-2,4-pyrimidinediamine asa by product was observed. ¹H NMR (CDCl₃): δ1.64-1.96 (m, 8H), 2.32-2.46(m, 4H), 4.31 (m, J=7.8 Hz, 1H), 4.50 (m, J=7.8 Hz, 1H), 4.99 (br, 2H),7.63 (d, J=3.6 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 172.68; LCMS: ret.time: 8.35 min.; purity: 96.68%; MS (m/e): 237.20 (MH⁺). 7.4.274N4-[4-(4-Acetylpiperazino)phenyl]-N2-cyclopropyl-5-fluoro-2,4-pyrimidinediamine(R945381) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine (300 mg, 1.8 mmol) and4-(4-acetylpiperazino)aniline (300 mg) were reacted to yieldN4-[4-(4-acetylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine.In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,cyclopropylamine (150 mg) andN4-[4-(4-acetylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(100 mg) were reacted to giveN4-[4-(4-acetylpiperazino)phenyl]-N2-cyclopropyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.73 (m, 2H), 0.84 (m, 2H), 2.18 (s, 3H), 2.76 (m,J=3.3 Hz, 1H), 3.23 (p, J=5.4 Hz, 4H), 3.68 (t, J=5.1 Hz, 2H), 3.82 (t,J=5.1 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 7.45 (d, J=3.0 Hz, 1H), 7.65 (d,J=5.1 Hz, 1H), 7.71 (d, J=9.0 Hz, 2H), 9.70 (br, 1H); ¹⁹F NMR (282 MHz,CDCl₃): δ- 166.00; LCMS: ret. time: 6.50 min.; purity: 93.56%; MS (m/e):371.24 (MH⁺). 7.4.275N4-[4-(4-Acetylpiperazino)phenyl]-N2-cyclobutyl-5-fluoro-2,4-pyrimidinediamine(R945382) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,cyclobutylamine (150 mg) andN4-[4-(4-acetylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine(100 mg) were reacted to giveN4-[4-(4-acetylpiperazino)phenyl]-N2-cyclobutyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.69-1.88 (m, 2H), 2.07-2.37 (m, 4H), 2.18 (s, 3H),3.25 (p, J=5.4 Hz, 4H), 3.68 (t, J=5.1 Hz, 2H), 3.83 (t, J=5.1 Hz, 2H),4.27 (m, J=7.2 Hz, 1H), 6.99 (d, J=9.3 Hz, 2H), 7.40 (br, 1H), 7.55 (d,J=9.0 Hz, 2H), 7.62 (d, J=5.1 Hz, 1H), 9.69 (br, 1H); ¹⁹F NMR (282 MHz,CDCl₃): δ- 166.57; LCMS: ret. time: 7.23 min.; purity: 89.04%; MS (m/e):385.25 (MH⁺). 7.4.276N2-[4-(N-Acetyl-N-methylamino)phenyl]-N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine(R945383) In a manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine (400 mg, 2.4 mmol) and cyclobutylamine(200 mg) were reacted at room temperature to yield2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine. In a manner similarto the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(N-acetylN-methylamino)aniline (100 mg) and2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN2-[4-(N-acetyl-N-methylamino)phenyl]-N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.75-2.02 (m, 4H), 1.88 (s, 3H), 2.41-2.51 (m, 2H),3.24 (s, 3H), 4.53 (m, J=7.8 Hz, 1H), 5.17 (d, J=6.3 Hz, 1H), 7.06 (br,1H), 7.10 (d, J=8.7 Hz, 2H), 7.63 (d, J=9.0 Hz, 2H), 7.78 (d, J=3.3 Hz,1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 168.52; LCMS: ret. time: 7.41 min.;purity: 97.56%; MS (m/e): 330.19 (MH⁺). 7.4.277cis/trans-N4-[4-[4-(tert-Butoxycarbonylamino)cyclohexyloxy]-3-chlorophenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945384) cis/trans-4-Aminocyclohexanol hydrogen chloride salt (10 g),di-tert-butyl dicarbonate (20 g) and sodium bicarbonate (20 g) weredissolved in THF (50 mL) and water (50 mL). The reaction solution wasstirred at rt overnight. The solution was extracted with ethyl acetate(100 mL) and the organic layer was evaporated to give4-tert-butoxycarbonylamino-cyclohexanol.cis/trans-4-tert-Butoxycarbonylaminocyclohexanol (10 g) was dissolved indichloromethane (100 mL). P-Tolunesulfonyl chloride (10 g), DMAP (5 g)and triethylamine (10 mL) were added to the solution. It was stirred atrt overnight. The reaction mixture was washed with 1N HCl aq. (3 × 100mL), dried and evaporated to givecis/trans-O-p-tolunesulfonyl-4-tert-butoxycarbonylaminocyclohexanol.cis/trans-O-p-Tolunesulfonyl-4-tert-butoxycarbonylaminocyclohexanol (10g), 2-chloro-4-nitrophenol (10 g) and potassium carbonate (10 g) wereheated at 60° C. in DMF (50 mL) for 4 h. The solution was diluted withethyl acetate (100 mL) and washed with water (3 × 100 mL). The organiclayer was dried, evaporated to give4-[4-(tert-butoxycarbonylamino)cyclohexyloxy]-3-chloronitrobenzene. Itwas reduced under hydrogenolysis conditions using 10% Pd-C in methanolat 60 psi for 1 h. The catalyst was filtered off. The filtrate wasevaporated to give4-[4-(tert-butoxycarbonylamino)cyclohexyloxy]-3-chloroaniline. In amanner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and4-[4-(tert-butoxycarbonylamino)cyclohexyloxy]-3-chloroaniline werereacted to yieldN4-[4-[4-(tert-butoxycarbonylamino)cyclohexyloxy]-3-chlorophenyl]-2-chloro-5-fluoro-4-pyrimidineamine.In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(methylaminocarbonylmethyleneoxy)aniline andN4-[4-[4-(tert-butoxycarbonylamino)cyclohexyloxy]-3-chlorophenyl]-2-chloro-5-fluoro-4-pyrimidineaminewere reacted to giveN4-[4-[4-(tert-butoxycarbonylamino)cyclohexyloxy]-3-chlorophenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.LCMS: ret. time: 12.83 min.; purity: 96.20%; MS (m/e): 615.32 (M⁺).7.4.278N2-[4-(4-Acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine(R945385) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-acetylpiperazino)aniline (100 mg) and2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN2-[4-(4-acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.72-1.99 (m, 4H), 2.13 (s, 3H), 2.39-2.49 (m, 2H),3.09 (p, J=5.1 Hz, 4H), 3.61 (t, J=5.1 Hz, 2H), 3.77 (t, J=5.1 Hz, 2H),4.51 (m, J=7.8 Hz, 1H), 5.10 (d, J=6.9 Hz, 1H), 6.85 (br, 1H), 6.90 (d,J=9.0 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H), 7.73 (d, J=3.3 Hz, 1H); ¹⁹F NMR(282 MHz, CDCl₃): δ- 170.01; LCMS: ret. time: 7.26 min.; purity: 90.49%;MS (m/e): 385.25 (MH⁺). 7.4.279N4-Cyclobutyl-5-fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine(R945386) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-methoxycarbonylpiperazino)aniline (100 mg) and2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN4-cyclobutyl-5-fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.72-1.85 (m, 2H), 1.88-1.99 (m, 2H), 2.38-2.48 (m,2H), 3.06 (t, J=5.1 Hz, 4H), 3.62 (t, J=5.1 Hz, 4H), 3.72 (s, 3H), 4.51(m, J=7.8 Hz, 1H), 5.09 (d, J=6.3 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 6.91(br, 1H), 7.45 (d, J=9.0 Hz, 2H), 7.73 (d, J=3.3 Hz, 1H); ¹⁹F NMR (282MHz, CDCl₃): δ- 170.12; LCMS: ret. time: 8.48 min.; purity: 94.18%; MS(m/e): 401.21 (MH⁺). 7.4.280N4-Cyclobutyl-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945387) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(methylaminocarbonylmethyleneoxy)aniline (100 mg) and2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine (100 mg) were reactedto giveN4-cyclobutyl-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.71 (m, 2H), 2.14 (m, 2H), 2.25 (m, 2H), 2.64 (d,J=4.2 Hz, 3H), 4.45 (s, 2H), 4.51 (m, 1H), 6.70 (dd, J=8.1 Hz, 1H), 7.13(d, J=8.1 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 7.32 (t, 1H), 8.03 (d, J=4.5Hz, 1H), 8.10 (d, J=5.4 Hz, 1H), 9.04 (br, 1H), 10.18 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ- 163.00; LCMS: ret. time: 7.50 min.; purity:95.47%; MS (m/e): 346.20 (MH⁺). 7.4.281N2-[3-(N-Cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945389) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(N-cyclobutylaminocarbonylmethyleneoxy)aniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-[3-(N-cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.53-1.65 (m, 2H), 1.90-2.03 (m, 2H), 2.07-2.17 (m,2H), 4.25 (q, J=8.1 Hz, 1H), 4.32 (s, 2H), 4.61 (s, 2H), 6.46 (dd, J=1.8and 8.1 Hz, 1H), 7.10 (t, J=8.1 Hz,1H), 7.23 (dd, J=0.9 and 8.4 Hz, 1H),7.38 (m, 2H), 7.60 (d, J=8.7 Hz, 1H), 8.13 (d, J=3.6 Hz, 1H), 8.22 (d,J=8.1 Hz, 1H), 9.23 (s, 1H), 9.26 (s, 1H), 11.12 (s, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ- 163.26; LCMS: ret. time: 9.98 min.; purity: 92.21%; MS(m/e): 480.25 (MH⁺). 7.4.282N2-[3-(N-Cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945390) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(N-cyclopropylaminocarbonylmethyleneoxy)aniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-[3-(N-cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ0.47 (m, 2H), 0.61 (m, 2H), 2.66 (m, J=3.6 Hz, 1H),4.32 (s, 2H), 4.62 (s, 2H), 6.44 (dd, J=2.4 and 7.5 Hz, 1H), 7.09 (t,J=8.1 Hz, 1H), 7.22 (dd, J=0.9 and 8.1 Hz, 1H), 7.37 (m, 2H), 7.59 (d,J=8.4 Hz, 1H), 8.05 (d, J=4.5 Hz, 1H), 8.13 (d, J=3.6 Hz, 1H), 9.22 (s,1H), 9.26 (s, 1H), 11.12 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 163.27;LCMS: ret. time: 8.89 min.; purity: 83.29%; MS (m/e): 466.24 (MH⁺).7.4.283N2-[4-(4-Acetylpiperazino)phenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945391) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-acetylpiperazino)aniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-[4-(4-acetylpiperazino)phenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ2.02 (s, 3H), 2.96 (t, J=5.1 Hz, 2H), 3.02 (t, J=5.1Hz, 2H), 3.55 (br, 4H), 4.62 (s, 2H), 6.84 (d, J=9.0 Hz, 2H), 7.36 (d,J=8.4 Hz, 1H), 7.48 (d, J=9.0 Hz, 2H), 7.57 (d, J=8.7 Hz, 1H), 8.07 (d,J=3.6 Hz, 1H), 9.01 (s, 1H), 9.13 (s, 1H), 11.14 (s, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ- 164.84; LCMS: ret. time: 7.29 min.; purity: 88.46%; MS(m/e): 479.27 (MH⁺). 7.4.2845-Fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945392) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-methoxycarbonylpiperazino)aniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-N4-(2H-3-oxo-4H-5-pyrid[1,4]-oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ2.98 (t, J=5.1 Hz, 4H), 3.48 (t, J=5.1 Hz, 4H), 3.60(s, 3H), 4.62 (s, 2H), 6.83 (d, J=9.3 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H),7.47 (d, J=9.0 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 8.06 (d, J=3.6 Hz, 1H),9.01 (s, 1H), 9.13 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 164.84; LCMS:ret. time: 8.61 min.; purity: 83.00%; MS (m/e): 495.25 (MH⁺). 7.4.285N4-Cyclobutyl-N2-(3-cyclopropylaminocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945393) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(N-cyclopropylaminocarbonylmethyleneoxy)aniline (100 mg) and2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine (50 mg) were reactedto giveN4-cyclobutyl-N2-[3-(N-cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ0.58 (m, 2H), 0.80-0.90 (m, 2H), 1.78-1.89 (m, 2H),1.94-2.07 (m, 2H), 2.43-2.53 (m, 2H), 2.78 (m, J=3.6 Hz, 1H), 4.49 (s,2H), 4.56 (m, J=7.8 Hz, 1H), 5.30 (br, 1H), 6.53 (ddd, J=0.9 and 2.7 and8.1 Hz, 1H), 6.66 (br, 1H), 7.01 (dd, J=1.2 and 8.1 Hz, 1H), 7.21 (t,J=8.1 Hz, 1H), 7.39 (br, 1H), 7.55 (t, J=2.1 Hz, 1H), 7.76 (d, J=3.6 Hz,1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 168.10; LCMS: ret. time: 8.29 min.;purity: 86.71%; MS (m/e): 372.24 (MH⁺). 7.4.286N4-Cyclobutyl-N2-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine(R945394) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,4-dichloroaniline (100 mg) and2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine (50 mg) were reactedto giveN4-cyclobutyl-N2-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine. ¹HNMR (DMSO-d₆): δ1.65-1.77 (m, 2H), 2.07-2.20 (m, 2H), 2.24-2.33 (m, 2H),4.42 (m, J=7.8 Hz, 1H), 7.44 (dd, J=2.4 and 8.7 Hz, 1H), 7.57 (d, J=8.7Hz, 1H), 8.12 (d, J=5.1 Hz, 1H), 8.16 (d, J=2.7 Hz, 1H), 8.99 (br, 1H),10.49 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 162.52; LCMS: ret. time:13.61 min.; purity: 89.20%; MS (m/e): 327.10 (MH⁺). 7.4.287N2-(3-Chloro-4-methoxyphenyl)-N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine(R945395) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-chloro-4-methoxyaniline (100 mg) and2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine (50 mg) were reactedto giveN2-(3-chloro-4-methoxyphenyl)-N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.63-1.75 (m, 2H), 2.08-2.31 (m, 4H), 3.83 (s, 3H),4.40 (m, J=7.8 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 7.34 (dd, J=2.4 and 8.7Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 8.10 (d, J=5.4 Hz, 1H), 9.17 (br, 1H),10.32 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 162.93; LCMS: ret. time:9.87 min.; purity: 90.17%; MS (m/e): 323.15 (MH⁺). 7.4.288N4-Cyclobutyl-N2-[3-(N-cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(R945396) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(N-cyclobutylaminocarbonylmethyleneoxy)aniline (100 mg) and2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine (50 mg) were reactedto giveN4-cyclobutyl-N2-[3-(N-cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ1.56-1.88 (m, 6H), 1.96-2.09 (m, 2H), 2.13-2.31 (m,4H), 4.28 (m, J=8.1 Hz, 1H), 4.32 (s, 2H), 4.40 (m, J=8.1 Hz, 1H), 6.62(ddd, J=1.2 and 2.1 and 8.1 Hz, 1H), 7.09-7.20 (m, 3H), 7.59 (d, J=4.8Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃): δ- 162.52; LCMS: ret. time: 9.39min.; purity: 94.65%; MS (m/e): 386.26 (MH⁺). 7.4.289N4-Cyclobutyl-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R945397) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,5-dichloro-4-methoxyaniline (100 mg) and2-chloro-N4-cyclobutyl-5-fluoro-4-pyrimidineamine (50 mg) were reactedto giveN4-cyclobutyl-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.63-1.76 (m, 2H), 2.07-2.33 (m, 4H), 3.78 (s, 3H),4.41 (m, J=7.8 Hz, 1H), 7.81 (s, 2H), 8.08 (d, J=5.1 Hz, 1H), 8.82 (br,1H), 10.21 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 163.16; LCMS: ret.time: 13.63 min.; purity: 92.88%; MS (m/e): 357.10 (MH⁺). 7.4.290N2-(3,4-Dichlorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945398) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,4-dichloroaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3,4-dichlorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ4.63 (s, 2H), 7.39-7.42 (m, 3H), 7.52 (dd, J=2.4 and8.7 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.18 (d, J=3.6 Hz, 1H), 9.46 (s,1H), 9.59 (s, 1H), 11.17 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 162.48;LCMS: ret. time: 13.30 min.; purity: 90.24%; MS (m/e): 421.07 (MH⁺).7.4.291N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945399) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-chloro-4-methoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ3.76 (s, 3H), 4.62 (s, 2H), 7.00 (d, J=9.0 Hz, 1H),7.40 (d, J=8.7 Hz, 1H), 7.47 (m, 2H), 7.80 (d, J=2.4 Hz, 1H), 8.12 (d,J=3.3 Hz, 1H), 9.22 (s, 1H), 9.27 (s, 1H), 11.15 (s, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ- 163.98; LCMS: ret. time: 10.38 min.; purity: 91.61%;MS (m/e): 417.14 (MH⁺). 7.4.292N2-(3,5-Dichloro-4-methoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945400) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,5-dichloro-4-methoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ3.72 (s, 3H), 4.55 (s, 2H), 7.30 (d, J=8.4 Hz, 1H),7.35 (d, J=8.4 Hz, 1H), 7.75 (s, 2H), 8.14 (d, J=3.6 Hz, 1H), 9.48 (s,1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 162.65. 7.4.293N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945401) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,5-dimethoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ3.64 (s, 6H), 4.62 (s, 2H), 6.06 (t, J=2.4 Hz, 1H),6.92 (d, J=2.4 Hz, 2H), 7.32 (d, J=8.7 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H),8.13 (d, J=3.6 Hz, 1H), 9.18 (s, 1H), 9.24 (s, 1H), 11.11 (s, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ- 163.28; LCMS: ret. time: 10.41 min.; purity:97.00%; MS (m/e): 413.19 (MH⁺). 7.4.2945-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945402) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-fluoro-4-methoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ3.75 (s, 3H), 4.62 (s, 2H), 6.99 (t, J=9.3 Hz, 1H),7.26 (dd, J=2.4 and 9.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 7.66 (dd, J=2.7 and 14.4 Hz, 1H), 8.11 (d, J=3.3 Hz, 1H), 9.24(s, 1H), 9.32 (s, 1H), 11.15 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ-163.98, - 134.90; LCMS: ret. time: 9.84 min.; purity: 93.66%; MS (m/e):401.18 (MH⁺). 7.4.295cis/trans-N4-[4-(4-Aminocyclohexyloxy)-3-chlorophenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945403)cis/trans-N4-{4-[4-(tert-Butoxycarbonylamino)cyclohexyloxy]-3-chlorophenyl}-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminewas deprotected under acidic condition (trifluoroacetic acid) to givecis/trans-N4-[4-(4-aminocyclohexyloxy)-3-chlorophenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 7.06 min.; purity: 92.49%; MS (m/e): 513.43 (M⁻).7.4.2965-Fluoro-N2-(4-methoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945404) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-methoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-(4-methoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ3.69 (s, 3H), 4.63 (s, 2H), 6.79 (d, J=9.0 Hz, 2H),7.35 (d, J=8.4 Hz, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.53 (d, J=9.0 Hz, 1H),8.07 (d, J=3.3 Hz, 1H), 9.05 (s, 1H), 9.18 (s, 1H), 11.13 (s, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ- 175.00; LCMS: ret. time: 8.85 min.; purity:100%; MS (m/e): 383.25 (MH⁺). 7.4.297N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945405) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,4-ethylenedioxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ4.16 (q, J=2.1 Hz, 4H), 4.62 (s, 2H), 6.67 (d, J=8.7Hz, 1H), 6.98 (dd, J=2.4 and 9.0 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 7.34(d, J=8.4 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 8.07 (d, J=3.6 Hz, 1H), 9.05(s, 1H), 9.21 (s, 1H), 11.11 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ-174.73; LCMS: ret. time: 8.94 min.; purity: 97.69%; MS (m/e): 411.26(MH⁺). 7.4.2985-Fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(4-trifluoromethoxyphenyl)-2,4-pyrimidinediamine(R945406) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-trifluoromethoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(4-trifluoromethoxyphenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ4.64 (s, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.7Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.73 (d, J=9.0 Hz, 2H), 8.14 (d, J=3.3Hz, 1H), 9.38 (s, 1H), 9.45 (s, 1H), 11.18 (s, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ- 173.29, - 68.81; LCMS: ret. time: 12.95 min.; purity: 100%;MS (m/e): 437.25 (MH⁺). 7.4.299N2-(4-Ethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945407) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-ethoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(4-ethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.30 (t, J=6.9 Hz, 3H), 3.94 (q, J=6.9 Hz, 2H), 4.63(s, 2H), 6.77 (d, J=8.7 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.48 (d, J=9.0Hz, 2H), 7.54 (d, J=8.7 Hz, 1H), 8.06 (d, J=3.6 Hz, 1H), 9.04 (s, 1H),9.17 (s, 1H), 11.14 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 175.00;LCMS: ret. time: 9.87 min.; purity: 90.82%; MS (m/e): 397.28 (MH⁺).7.4.300N2-(4-Butoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945408) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-butoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(4-butoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ0.93 (t, J=7.5 Hz, 3H), 1.42 (hept, J=7.5 Hz, 2H),1.66 (p, J=6.9 Hz, 2H), 3.89 (t, J=6.3 Hz, 2H), 4.62 (s, 2H), 6.78 (d,J=8.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.48 (d, J=9.3 Hz, 2H), 7.54 (d,J=8.7 Hz, 1H), 8.06 (d, J=3.6 Hz, 1H), 9.04 (s, 1H), 9.17 (s, 1H), 11.14(s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 175.02; LCMS: ret. time: 12.12min.; purity: 95.36%; MS (m/e): 425.31 (MH⁺). 7.4.3015-Fluoro-N2-(4-phenoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945409) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-phenoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-(4-phenoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ4.60 (s, 2H), 6.91 (d, J=9.0 Hz, 4H), 7.05 (t, J=7.2Hz, 1H), 7.32 (m, 3H), 7.52 (d, J=8.4 Hz, 1H), 7.63 (d, J=9.0 Hz, 2H),8.10 (d, J=3.6 Hz, 1H), 9.27 (s, 2H), 11.14 (s, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ- 174.19; LCMS: ret. time: 12.69 min.; purity: 100%; MS(m/e): 445.27 (MH⁺). 7.4.302N2-(4-Benzyloxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945410) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-benzyloxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(4-benzyloxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ4.62 (s, 2H), 5.03 (s, 2H), 6.86 (d, J=9.0 Hz, 2H),7.31-7.51 (m, 9H), 8.06 (d, J=3.3 Hz, 1H), 9.05 (s, 1H), 9.15 (s, 1H),11.13 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 170.56; LCMS: ret. time:12.02 min.; MS (m/e): 459.33 (MH⁺). 7.4.303cis/trans-N4-[3-Chloro-4-[4-(N-ethylamino)cyclohexyloxy]phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(R945411)cis/trans-4-[4-(tert-Butoxycarbonylamino)cyclohexyloxy]-3-chloronitrobenzene(5 g) was deprotected using TFA (10 mL) and dichloromethane (10 mL) togive cis/trans-4-[4-(amino)cyclohexyloxy]-3-chloronitrobenzene. It wascapped with acetyl chloride in dichloromethane and triethylamine to givecis/trans-4-[4-(acetylamino)cyclohexyloxy]-3-chloronitrobenzene. It wasthen refluxed with boron hydride methyl sulfide complex in THF for 1 hto givecis/trans-3-chloro-4-[4-(N-ethylamino)cyclohexyloxy]nitrobenzene. It wasreduced under hydrogenolysis conditions using 10% Pd-C in methanol at 60psi for 1 h. The catalyst was filtered off. The filtrate was evaporatedto give cis/trans-3-chloro-4-[4-(N-ethylamino)cyclohexyloxy]aniline. Ina manner similar to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine andcis/trans-3-chloro-4-[4-(N-ethylamino)cyclohexyloxy]aniline were reactedto yieldcis/trans-2-chloro-N4-[3-chloro-4-[4-(N-ethylamino)cyclohexyloxy]phenyl]-5-fluoro-4-pyrimidineamine.In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(methylaminocarbonylmethyleneoxy)aniline andcis/trans-2-chloro-N4-[3-chloro-4-[4-(N-ethylamino)cyclohexyloxy]phenyl]-5-fluoro-4-pyrimidineaminewere reacted to givecis/trans-N4-{3-chloro-4-[4-(N-ethylamino)cyclohexyloxy]phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine.LCMS: ret. time: 7.65 min.; purity: 78.88%; MS (m/e): 544 (MH⁺). 7.4.3045-Fluoro-N2-(4-morpholinophenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945412) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-morpholinoaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-(4-morpholinophenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ3.00 (t, J=4.8 Hz, 4H), 3.71 (t, J=4.8 Hz, 4H), 4.62(s, 2H), 6.81 (d, J=9.0 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.46 (d, J=9.3Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 8.05 (d, J=3.6 Hz, 1H), 9.00 (s, 1H),9.13 (s, 1H), 11.13 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 175.15;LCMS: ret. time: 8.08 min.; purity: 92.97%; MS (m/e): 438.32 (MH⁺).7.4.3055-Fluoro-N2-(4-isopropoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945413) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-isopropoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-(4-isopropoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.22 (d, J=6.3 Hz, 6H), 4.48 (p, J=6.0 Hz, 1H), 4.62(s, 2H), 6.76 (d, J=9.0 Hz, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.47 (d, J=9.0Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 8.06 (d, J=3.6 Hz, 1H), 9.02 (s, 1H),9.15 (s, 1H), 11.12 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 175.03;LCMS: ret. time: 10.52 min.; purity: 100%; MS (m/e): 411.32 (MH⁺).7.4.306N4-(2,2-Difluoro-2H-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminep-Toluenesulfonic Acid Salt (R945414)N4-(2,2-Difluoro-2H-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(118 mg, 0.25 mmol) was suspended in acetonitrile (4 mL) and methanol (4mL). At 0° C., the aq. solution (4 mL) of p-toluenesulfonic acidmonohydrate (47.5 mg, 0.25 mmol) was added. The reaction solution wasshaken at room temperature for 5 minutes and lyophilized to dryness. Theresulting solid was recrystallized from methanol and ethyl acetate togiveN4-(2,2-difluoro-2H-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminep-toluenesulfonic acid salt as a white solid.¹H NMR (DMSO-d₆): δ2.28 (s,3H), 2.63 (d, J=4.8 Hz, 3H), 4.33 (s, 2H), 6.58 (p, J=3.0 Hz, 1H), 7.09(d, J=8.4 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 7.22 (s, 1H), 7.26 (d, J=8.7Hz, 1H), 7.36 (d, J=2.7 Hz, 1H), 7.46 (d, J=7.8 Hz, 2H), 7.53 (dd, J=2.4and 8.7 Hz, 1H), 7.95 (d, J=4.8 Hz, 1H), 8.19 (d, J=4.5 Hz, 1H), 9.60(s, 1H), 10.11 (s, 1H), 11.98 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ-162.01, - 76.80; LCMS: ret. time: 9.80 min.; purity: 100%; MS (m/e):475.32 (MH⁺). 7.4.307N4-(2,2-Difluoro-2H-3-oxo-4H-benz[1.4]oxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamineBenzenesulfonic Acid Salt (R945415) In a manner similar to thepreparation ofN4-(2,2-difluoro-2H-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminep-toluenesulfonic acid salt,N4-[2,2-difluoro-2H-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine(118 mg, 0.25 mmol) and benzenesulfonic acid (60 mg) were reacted togiveN4-(2,2-difluoro-2H-3-oxo-4H-benz[1.4]oxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediaminebenzenesulfonic acid salt as a white solid. ¹H NMR (DMSO-d₆): δ2.63 (d,J=4.5 Hz, 3H), 4.33 (s, 2H), 6.56 (dt, J=2.4 and 6.9 Hz, 1H), 7.10-7.37(m, 8H), 7.52-7.59 (m, 3H), 7.96 (d, J=4.5 Hz, 1H), 8.18 (d, J=4.5 Hz,1H), 9.53 (s, 1H), 10.03 (s, 1H), 11.98 (s, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ- 162.30, - 76.83; LCMS: ret. time: 9.79 min.; purity: 100%;MS (m/e): 475.34 (MH⁺). 7.4.308N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl]-5-fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine(R945416) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-methoxycarbonylpiperazino)aniline (100 mg) and2-chloro-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine(50 mg) were reacted to giveN4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl]-5-fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.43 (s, 6H), 2.99 (t, J=5.1 Hz, 4H), 3.49 (t, J=5.1Hz, 4H), 3.61 (s, 3H), 6.82 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.4 Hz, 1H),7.47 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.1 Hz, 1H), 8.06 (d, J=3.6 Hz, 1H),9.02 (s, 1H), 9.14 (s, 1H), 11.08 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ- 164.38; LCMS: ret. time: 10.24 min.; purity: 100%; MS (m/e): 523.45(MH⁺). 7.4.309N2-[4-(N-Acetyl-N-methylamino)phenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R945417) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(N-acetyl-N-methylamino)aniline (100 mg) and2-chloro-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine(50 mg) were reacted to giveN2-[4-(N-acetyl-N-methylamino)phenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.43 (s, 6H), 1.73 (s, 3H), 3.08 (s, 3H), 7.11 (d,J=8.7 Hz, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.68 (d,J=8.7 Hz, 2H), 8.13 (d, J=3.6 Hz, 1H), 9.35 (s, 1H), 9.40 (s, 1H), 11.12(s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 162.87; LCMS: ret. time: 10.03min.; purity: 100%; MS (m/e): 452.26 (MH⁺). 7.4.310N2-[4-(N-Acetyl-N-ethylamino)phenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R945418) In a manner similar to the preparation of4-(4-methoxycarbonylpiperazino)nitrobenzene, N-ethyl-4-nitroaniline (1g) and acetyl chloride (1 mL) were reacted to yieldN-acetyl-N-ethyl-4-nitroaniline. ¹H NMR (CDCl₃): δ1.15 (t, J=7.2 Hz,3H), 1.94 (s, 3H), 3.81 (q, J=7.2 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 8.30(d, J=8.7 Hz, 2H). N-Acetyl-N-ethyl-4-nitroaniline was reduced underhydrogenolysis conditions using 10% Pd-C in methanol at 40 psi for 1 h.The catalyst was filtered off. The filtrate was evaporated to give4-(N-acetyl-N-ethylamino)aniline. ¹H NMR (CDCl₃): δ1.09 (t, J=7.2 Hz,3H), 1.82 (s, 3H), 3.68 (q, J=7.2 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 6.95(d, J=8.1 Hz, 2H). In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(N-acetyl-N-ethylamino)aniline (100 mg) and2-chloro-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine(50 mg) were reacted to giveN2-[4-(N-acetyl-N-ethylamino)phenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ0.97 (t, J=7.2 Hz, 3H), 1.43 (s, 6H), 1.68 (s, 3H),3.56 (q, J=6.9 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.40 (d, J=8.7 Hz, 1H),7.48 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.7 Hz, 2H), 8.13 (d, J=3.3 Hz, 1H),9.35 (s, 1H), 9.40 (s, 1H), 11.12 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ- 162.90; LCMS: ret. time: 10.51 min.; purity: 100%; MS (m/e): 466.25(MH⁺). 7.4.311N2-[4-(4-Acetylpiperazino)phenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R945419) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-acetylpiperazino)aniline (100 mg) and2-chloro-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine(50 mg) were reacted to giveN2-[4-(4-acetylpiperazino)phenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.43 (s, 6H), 2.03 (s, 3H), 2.96 (t, J=5.1 Hz, 2H),3.03 (t, J=4.8 Hz, 2H), 3.56 (m, 4H), 6.82 (d, J=9.0 Hz, 2H), 7.37 (d,J=8.4 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.1 Hz, 1H), 8.06 (d,J=3.6 Hz, 1H), 9.02 (s, 1H), 9.13 (s, 1H), 11.08 (s, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ- 164.40; LCMS: ret. time: 8.70 min.; purity: 97.70%; MS(m/e): 507.55 (MH⁺). 7.4.312N2-[4-(N-Acetyl-N-methylamino)phenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945420) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(N-acetyl-N-methylamino)aniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-[4-(N-acetyl-N-methylamino)phenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.74 (s, 3H), 3.09 (s, 3H), 4.64 (s, 2H), 7.13 (d,J=8.7 Hz, 2H), 7.40 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.69 (d,J=8.7 Hz, 2H), 8.13 (d, J=3.3 Hz, 1H), 9.34 (s, 1H), 9.39 (s, 1H), 11.16(s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 171.37; LCMS: ret. time: 9.14min.; purity: 91.43%; MS (m/e): 424.50 (MH⁺). 7.4.313N2-[4-(N-Acetyl-N-ethylamino)phenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945421) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(N-acetyl-N-ethylamino)aniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-[4-(N-acetyl-N-ethylamino)phenyl]-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ0.98 (t, J=6.9 Hz, 3H), 1.69 (s, 3H), 3.57 (q, J=6.9Hz, 2H), 4.63 (s, 2H), 7.08 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.4 Hz, 1H),7.50 (d, J=8.4 Hz, 1H), 7.69 (d, J=9.0 Hz, 2H), 8.13 (d, J=3.6 Hz, 1H),9.34 (s, 1H), 9.40 (s, 1H), 11.16 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ- 171.36; LCMS: ret. time: 9.26 min.; purity: 91.13%; MS (m/e): 438.27(MH⁺). 7.4.314N2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945422) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,4-dimethoxyaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3,4-dimethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ3.64 (s, 3H), 3.68 (s, 3H), 4.63 (s, 2H), 6.79 (d,J=9.0 Hz, 1H), 7.20-7.23 (m, 2H), 7.33 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.7Hz, 1H), 8.08 (d, J=3.6 Hz, 1H), 9.03 (s, 1H), 9.16 (s, 1H), 11.13 (s,1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 172.45; LCMS: ret. time: 8.35 min.;purity: 94.21%; MS (m/e): 413.30 (MH⁺). 7.4.315N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine(R945423) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-morpholinoaniline (100 mg) and2-chloro-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine(50 mg) were reacted to giveN4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.43 (s, 6H), 2.99 (t, J=4.8 Hz, 4H), 3.72 (t, J=4.8Hz, 4H), 6.80 (d, J=8.7 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.46 (d, J=9.0Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 8.06 (d, J=3.6 Hz, 1H), 9.00 (s, 1H),9.13 (s, 1H), 11.09 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 173.16;LCMS: ret. time: 9.59 min.; purity: 100%; MS (m/e): 466.28 (MH⁺).7.4.316N2-[3-(N-Cyclobutylamino)carbonylmethyleneoxyphenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R945424) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-(cyclobutylaminocarbonylmethyleneoxy)aniline (100 mg) and2-chloro-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine(50 mg) were reacted to giveN2-[3-(N-cyclobutylamino)carbonylmethyleneoxyphenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.42 (s, 6H), 1.57-1.66 (m, 2H), 1.90-2.04 (m, 2H),2.12 (m, 2H), 4.25 (q, J=8.4 Hz, 1H), 4.33 (s, 2H), 6.46 (dd, J=1.8 and8.1 Hz, 1H), 7.08 (t, J=8.1 Hz,1H), 7.25 (dd, J=8.4 Hz, 1H), 7.35 (m,1H), 7.36 (d, J=9.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 8.12 (d, J=3.6 Hz,1H), 8.23 (d, J=7.5 Hz, 1H), 9.22 (s, 1H), 9.26 (s, 1H), 11.06 (s, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ- 171.41; LCMS: ret. time: 11.46 min.;purity: 97.65%; MS (m/e): 508.45 (MH⁺). 7.4.3175-Fluoro-N2-[4-(4-methylpiperazino)phenyl]-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945426) 1-(4-Nitrophenyl)piperazine (1 g), iodomethane (0.3 mL) andsodium hydride(500 mg) in THF (10 mL) were reacted overnight at roomtemperature. The solution was diluted with water. The yellowprecipitation was collected by filtration, washed with water to give4-(4-methylpiperazino)nitrobenzene as yellow solid. ¹H NMR (CDCl₃):δ2.45 (s, 3H), 2.69 (t, J=5.1 Hz, 4H), 3.52 (t, J=5.1 Hz, 4H), 6.83 (d,J=9.3 Hz, 2H), 8.12 (d, J=9.3 Hz, 2H).4-(4-Methylpiperazino)nitrobenzene was reduced under hydrogenolysisconditions using 10% Pd-C in methanol at 40 psi for 1 h. The catalystwas filtered off. The filtrate was evaporated to give4-(4-methylpiperazino)aniline. ¹H NMR (CDCl₃): δ2.47 (s, 3H), 2.75 (t,J=5.1 Hz, 4H), 3.16 (t, J=5.1 Hz, 4H), 6.65 (d, J=9.0 Hz, 2H), 6.81 (d,J=8.7 Hz, 2H). In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-methylpiperazino)aniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ2.85 (s, 3H), 3.16 (m, 2H), 3.48 (m, 4H), 3.69 (m,2H), 4.63 (s, 2H), 6.87 (d, J=9.0 Hz, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.50(d, J=9.0 Hz, 2H), 7.54 (d, J=8.1 Hz, 1H), 8.07 (d, J=3.6 Hz, 1H), 9.08(s, 1H), 9.21 (s, 1H), 11.16 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ-172.68; LCMS: ret. time: 5.67 min.; purity: 100%; MS (m/e): 451 (MH⁺).7.4.318N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine(R945427) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,4-(4-methylpiperazino)aniline (100 mg) and2-chloro-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine(50 mg) were reacted to giveN4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.43 (s, 6H), 2.71 (s, 3H), 3.16 (br, 8H), 6.84 (d,J=9.0 Hz, 2H), 7.37 (d, J=8.4 Hz, 1H), 7.49 (d, J=9.0 Hz, 2H), 7.54 (d,J=8.4 Hz, 1H), 8.07 (d, J=3.6 Hz, 1H), 9.05 (s, 1H), 9.18 (s, 1H), 11.10(s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 172.96; LCMS: ret. time: 7.08min.; purity: 91.96%; MS (m/e): 479.25 (MH⁺). 7.4.319N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945432) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,5-dimethylaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3,5-dimethylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ2.17 (s, 6H), 4.62 (s, 2H), 6.52 (s, 1H), 7.22 (s,2H), 7.34 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 8.11 (d, J=3.6 Hz,1H), 9.10 (s, 1H), 9.19 (s, 1H), 11.14 (s, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ- 172.16; LCMS: ret. time: 11.34 min.; purity: 90.04%; MS(m/e): 381.23 (MH⁺). 7.4.320N2-(3,5-Dimethylphenyl)-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R945433) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,5-dimethylaniline (100 mg) and2-chloro-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine(50 mg) were reacted to giveN2-(3,5-dimethylphenyl)-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.42 (s, 6H), 2.16 (s, 6H), 6.51 (s, 1H), 7.23 (s,2H), 7.35 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 8.11 (d, J=3.6 Hz,1H), 9.10 (s, 1H), 9.18 (s, 1H), 11.08 (s, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ- 172.19; LCMS: ret. time: 13.05 min.; purity: 95.71%; MS(m/e): 409.30 (MH⁺). 7.4.3215-Fluoro-N2-(3-isopropylphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945434) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-isopropylaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-(3-isopropylphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.15 (d, J=6.9 Hz, 6H), 2.74 (p, J=6.9 Hz, 1H), 4.63(s, 2H), 6.76 (d, J=7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 7.34 (d, J=8.7Hz, 1H), 7.42 (s, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H),8.11 (d, J=3.6 Hz, 1H), 9.15 (s, 1H), 9.21 (s, 1H), 11.15 (s, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ- 172.02; LCMS: ret. time: 12.40 min.; purity:92.20%; MS (m/e): 395.28 (MH⁺). 7.4.322N2-(3-Chloro-4-methylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945439) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-chloro-4-methylaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3-chloro-4-methylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ2.22 (s, 3H), 4.63 (s, 2H), 7.13 (d, J=8.7 Hz, 1H),7.38 (m, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.83 (d, J=2.1 Hz, 1H), 8.13 (d,J=3.3 Hz, 1H), 9.31 (s, 1H), 9.33 (s, 1H), 11.13 (s, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ- 171.47; LCMS: ret. time: 12.66 min.; purity: 94.85%;MS (m/e): 401.13 (MH⁺). 7.4.3235-Fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945440) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-methoxy-5-trifluoromethylaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ3.74 (s, 3H), 4.63 (s, 2H), 6.72 (s, 1H), 7.32 (d,J=8.4 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.56 (s, 1H), 7.64 (s, 1H), 8.18(d, J=3.3 Hz, 1H), 9.36 (s, 1H), 9.55 (s, 1H), 11.12 (s, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ- 170.42; LCMS: ret. time: 13.14 min.; purity:86.65%; MS (m/e): 451.30 (MH⁺). 7.4.3245-Fluoro-N2-(indol-6-yl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945443) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,6-aminoindol (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to give5-fluoro-N2-(indol-6-yl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ4.62 (s, 2H), 6.30 (s, 1H), 7.17 (m, 2H), 7.29 (d,J=8.7 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.82 (s,1H), 8.10 (d, J=3.6 Hz, 1H), 9.08 (s, 1H), 9.11 (s, 1H), 10.84 (s, 1H),11.11 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 172.73; LCMS: ret. time:8.52 min.; purity: 81.74%; MS (m/e): 392.30 (MH⁺). 7.4.325N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine(R945444) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,6-aminoindol (100 mg) and2-chloro-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamine(50 mg) were reacted to giveN4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.42 (s, 6H), 6.30 (s, 1H), 7.18 (m, 2H), 7.29 (d,J=8.4 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.80 (s,1H), 8.10 (d, J=3.6 Hz, 1H), 9.02 (s, 1H), 9.09 (s, 1H), 10.84 (s, 1H),11.04 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 172.86; LCMS: ret. time:9.91 min.; purity: 98.01%; MS (m/e): 420.18 (MH⁺). 7.4.326N2-(3,5-Dichlorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945454) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,5-dichloroaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3,5-dichlorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ4.62 (s, 2H), 6.99 (t, J=1.8 Hz, 1H), 7.38 (s, 2H),7.70 (d, J=2.1 Hz, 2H), 8.19 (d, J=3.6 Hz, 1H), 9.52 (s, 1H), 9.66 (s,1H), 11.17 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 170.19; LCMS: ret.time: 14.05 min.; purity: 85.53%; MS (m/e): 421.21 (MH⁺). 7.4.327N2-(3-Bromophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945455) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-bromoaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3-bromophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ4.63 (s, 2H), 7.02 (ddd, J=0.9 and 1.8 and 7.8 Hz,1H), 7.13 (t, J=8.1 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.1 Hz,1H), 7.52 (dd, J=0.9 and 8.1 Hz, 1H), 7.99 (t, J=1.8 Hz, 1H), 8.16 (d,J=3.6 Hz, 1H), 9.40 (s, 1H), 9.47 (s, 1H), 11.17 (s, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ- 170.91; LCMS: ret. time: 12.31 min.; purity: 100%; MS(m/e): 431.20 (MH⁺). 7.4.328N2-(3-tert-Butylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945456) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3-tert-butylaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3-tert-butylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ1.23 (s, 9H), 4.62 (s, 2H), 6.91 (d, J=8.1 Hz, 1H),7.11 (t, J=8.1 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.58 (s,1H), 7.63 (d, J=9.9 Hz, 1H), 8.11 (d, J=3.6 Hz, 1H), 9.12 (s, 1H), 9.16(s, 1H), 11.12 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 171.99; LCMS:ret. time: 13.16 min.; purity: 93.03%; MS (m/e): 409.29 (MH⁺). 7.4.329N2-(3,4-Difluorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R945458) In a manner similar to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,3,4-difluoroaniline (100 mg) and2-chloro-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine(50 mg) were reacted to giveN2-(3,4-difluorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ4.63 (s, 2H), 7.27 (m, 2H), 7.38 (s, 2H), 7.88 (ddd,J=2.7 and 8.1 and 14.1 Hz, 1H), 8.15 (d, J=3.6 Hz, 1H), 9.46 (s, 1H),9.48 (s, 1H), 11.17 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ- 162.44, -148.50, - 138.13; LCMS: ret. time: 11.63 min.; purity: 84.89%; MS (m/e):389.25 (MH⁺). Synthesis of Anilines 7.4.330(S)-2-Methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine To solution of2-amino-4-nitrophenol (6.6 g) in DMF (100 mL) at 0° C. was added 95% NaH(1 g) solid all at once. The solution was stirred at 0° C.for 20 minutesthen at room temperature for 1 hour. (S)-(−)-Methyl-2-chloropropionate(5 g) was added all at once and the reaction was heated with a refluxcondenser attached at 85° C. overnight. The reaction mixture wasconcentrated and the residue was partitioned between EtOAc and water.The aqueous phase was extracted with EtOAc and the combined organiclayers were washed three times with water and then once with brine,dried over MgSO4, filtered and the volume was minimized on the rotaryevaporater to about 15 mL. The residue was chromatographed EtOAc/hexanes1:4 isocratically. The pure fractions were combined and evaporated andthe crude product recrystallized from EtOAc/hexanes to yield(S)-2-methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine. ¹H NMR (DMSO-d₆): δ7.82(dd, 1H), 7.76 (d, 1H), 7.12 (d, 1H), 4.90 (q, 1H), 1.42 (d, 3H); LCMS:purity: 100 %; MS (m/e): 209 (MH⁺). 7.4.331(S)-6-Amino-2-methyl-3-oxo-4H-benz[1,4]oxazine To a solution of(S)-2-methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine (2.5 g) in 250 mLEtOH/EtOAc (1:1; v/v) was added 500 mg of 10% Pd/C (Degussa) and thereaction was hydrogenated in the Parr apparatus at 50 PSI for 1 hour.The reaction was filtered through a bed of celite, evaporated and driedin vacuo to yield the 2.3 g of(S)-6-Amino-2-methyl-3-oxo-4H-benz[1,4]oxazine. ¹H NMR (DMSO-d₆): δ6.60(d, 1H), 6.12 (m, 2H), 4.40 (q, 1H), 1.32 (d, 3H); LCMS: purity: 100 %;MS (m/e): 179 (MH⁺). 7.4.332(R)-2-Methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine In like manner to thesynthesis of (S)-2-methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine, thereaction of (R)-(+)-methyl-2-chloropropionate with 2-amino-4-nitrophenolgave (R)-2-methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine. ¹H NMR (DMSO-d₆):δ7.82 (dd, 1H), 7.76 (d, 1H), 7.12 (d, 1H), 4.90 (q, 1H), 1.42 (d, 3H);LCMS: purity: 100 %; MS (m/e): 209 (MH⁺). 7.4.333(R)-6-Amino-2-methyl-3-oxo-4H-benz[1,4]oxazine In like manner to thesynthesis of (S)-6-amino-2-methyl-3-oxo-4H-benz[1,4]oxazine, thehydrogenation of (R)-2-methyl-6-nitro-3-oxo-4H-benz[1,4]oxazine gave(R)-6-amino-2-methyl-3-oxo-4H-benz[1,4]oxazine. ¹H NMR (DMSO-d₆): δ6.60(d, 1H), 6.12 (m, 2H), 4.40 (q, 1H), 1.32 (d, 3H); LCMS: purity: 100 %;MS (m/e): 179 (MH⁺). 7.4.3347-Amino-4,4-dimethyl-1,3-dioxo-2H,4H-isoquinoline The material wasprepared according to the procedure outlined in J. Med Chem, 2002,45(16), 3394-3405. 7.4.335(±)-2-(2-Hydroxyethyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine To solution of2-Amino-4-nitrophenol (16.5 g) in DMF (100 mL) at 0° C. was added 95%NaH (3 g) solid all at once. The reaction mixture was stirred at 0° C.for 20 minutes then at room temperature for 1 hour. 2-Bromobutyrolactone(13.8 mL) was added to the reaction mixture and it was then heated at85° C. for overnight period with a reflux condenser attached. Thereaction mixturewas concentrated to approximately 25 mL and diluted with25 mL of MeOH. 400 mL of DI water was added with stirring and theprecipitated product was collected filtration and dried on the funnelfor 4 h to yield(±)-2-(2-hydroxyethyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine. ¹H NMR(DMSO-d₆): δ7.82 (dd, 1H), 7.75 (d, 1H), 7.18 (d, 1H), 4.90 (m, 1H),4.70 (t, 1H), 3.8 (m, 2H), 1.96 (m, 2H); LCMS: purity: 100 %; MS (m/e):239 (MH⁺). 7.4.336(±)-6-Amino-2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazine To a solutionof (±)-2-(2-hydroxyethyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine (1 g) inEtOH/EtOAc (100 mL; 1:1 v/v) was hydrogenated at 50 PSI in the presenceof 200 mg of 10% Pd/C (Degussa) to give(±)-6-amino-2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazine. ¹H NMR(DMSO-d₆): δ6.60 (d, 1H), 6.12 (m,, 2H), 4.58 (t, 1H), 4.40 (m, 1H),3.57 (m, 2H), 1.76 (m, 2H); LCMS: purity: 98 %; MS (m/e): 209 (MH⁺)7.4.337(S)-2-Chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, thereaction of 2,4-dichloro-5-fluoropyrimidine and(S)-6-amino-2-methyl-3-oxo-4H-benz[1,4]oxazine yielded(S)-2-Chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ8.2 (d, 1H), 7.21 (m, 2H), 6.95 (d, 1H), 4.62 (q,1H), 1.41 (d, 3H); LCMS: purity: 96 %; MS (m/e): 309 (MH⁺). 7.4.338N2-chloro-5-fluoro-N4-(2-(R)-methyl-1,4-benzoxazin-3-on-6-yl)-pyrimidineamine 7.4.339(R)-2-Chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, thereaction of 2,4-dichloro-5-fluoropyrimidine and(R)-6-amino-2-methyl-3-oxo-4H-benz[1,4]oxazine yielded(R)-2-Chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ8.2 (d, 1H), 7.21 (m, 2H), 6.95 (d, 1H), 4.62 (q,1H), 1.41 (d, 3H); LCMS: purity: 96 %; MS (m/e): 309 (MH⁺). 7.4.340(±)-2-Chloro-5-fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, thereaction of 2,4-dichloro-5-fluoropyrimidine and(±)-6-amino-2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazine yielded(±)-2-Chloro-5-fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ8.2 (d, 1H), 7.22 (m, 2H), 6.95 (d, 1H), 4.60 (m,1H), 3.56 (m, 2H), 1.87 (m, 2H); LCMS: purity: 94 %; MS (m/e): 339(MH⁺). 7.4.3412-Chloro-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-4-pyrimidineamineIn like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and7-Amino-4,4-dimethyl-2H,4H-1,3-dioxo-isoquinoline were reacted to yield2-chloro-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ8.38 (d, 1H), 8.05 (m, 2H), 7.78 (d, 1H), 1.47 (s,6H;); LCMS: purity: 94 %; MS (m/e): 335 (MH⁺). 7.4.342(S)-5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R909317) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(S)-2-Chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield(S)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.04 (d, 1H), 7.23 (m, 4H), 7.04 (t, 1H), 6.92 (d,1H), 6.53 (dd, 1H), 4.61 (q, 2H), 4.37 (s, 2H), 2.61 (d, 3H), 1.40 (d,3H); LCMS: purity: 96 %; MS (m/e): 453 (MH⁺) 7.4.343N4-(4,4-Dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethylenedioxyphenyl]-2,4-pyrimidinediamine(R909318) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-4-pyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yieldN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethylenedioxyphenyl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.30 (dd, 1H), 8.18 (m, 2H), 7.98 (m, 1H), 7.62 (d,1H), 7.38 (s, 1H), 7.22 (d, 1H), 7.04 (t, 1H), 6.43 (dd, 1H), 4.24 (s,2H), 2.61 (s, 3H), 1.44 (s, 6H); LCMS: purity: 92%; MS (m/e): 479 (MH⁺).7.4.344(R)-5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R909317) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(R)-2-Chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 3-(N-methylaminocarbonylmethyleneoxy)aniline were reacted to yield(R)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.04 (d, 1H), 7.23 (m, 4H), 7.04 (t, 1H), 6.92 (d,1H), 6.53 (dd, 1H), 4.61 (q, 2H), 4.37 (s, 2H), 2.61 (d, 3H), 1.40 (d,3H); LCMS: purity: 96 %; MS (m/e): 453 (MH⁺). 7.4.345N2-(3-Chloro-4-hydrox-5-methylyphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine(R909320) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-4-pyrimidineamineand 3-chloro-4-hydroxy-5-methylaniline were reacted to yieldN2-(3-chloro-4-hydrox-5-methylyphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.22 (d, 1H), 8.19 (d, 1H), 8.02 (dd, 1H), 7.62 (m,3H), 1.50 (s, 6H); LCMS: purity: 92%; MS (m/e): 456 (MH⁺). 7.4.346(S)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R909321) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(S)-2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 3-chloro-4-methoxyaniline were reacted to yield(S)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.12 (d, 1H), 7.41 (dd, 1H), 7.22 (m, 3H), 6.97 (m,1H), 4.61 (q, 1H), 3.78 (s, 3H), 1.40 (d, 3H); LCMS: purity: 97%; MS(m/e): 430 (MH⁺). 7.4.347(R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R909322) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(R)-2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 3-chloro-4-methoxyaniline were reacted to yield(R)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.12 (d, 1H), 7.41 (dd, 1H), 7.22 (m, 3H), 6.97 (m,1H), 4.61 (q, 1H), 3.78 (s, 3H), 1.40 (d, 3H); LCMS: purity: 97%; MS(m/e): 430 (MH⁺). 7.4.348N2-(3,5-Dimethoxyphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine (R909323) In like manner to the synthesisofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-4-pyrimidineamineand 3,5-dimethoxyaniline were reacted to yieldN2-(3,5-dimethoxyphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ8.18 (d, 1H), 8.05(m, 3H), 7.75 (m,, 3H), 3.30 (s, 6H), 1.52 (s, 6H); LCMS: purity: 91%;MS (m/e): 452 (MH⁺). 7.4.349(S)-N2-(3,5-Dichloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]-oxazin-6-yl)-2,4-pyrimidinediamine(R908946) In like manner to the synthesis ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(S)-N2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 3,5-dichloro-4-methoxyaniline were reacted to yield(S)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]-oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.07 (d, 1H), 7.78 (s, 2H), 7.09 (m, 2H), 6.95 (d,1H), 4.61 (q, 1H), 3.75 (s, 3H), 1.21 (d, 3H); LCMS: purity: 98%; MS(m/e): 465 (MH⁺). 7.4.350(R)-N2-(3,5-Dichloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]-oxazin-6-yl)-2,4-pyrimidinediamine(R908947) In like manner to the synthesis ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(R)-N2-chloro-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 3,5-dichloro-4-methoxyaniline were reacted to yield(R)-N2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]-oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.07 (d, 1H), 7.78 (s, 2H), 7.09 (m, 2H), 6.95 (d,1H), 4.61 (q, 1H), 3.75 (s, 3H), 1.21 (d, 3H); LCMS: purity: 98%; MS(m/e): 465 (MH⁺). 7.4.351(±)-N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine(R908950) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-4-pyrimidineamineand 3,5-dimethoxyaniline were reacted to yield(±)-N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.04 (d, 1H), 7.23 (m, 2H), 6.95 (m, 3H), 6.02 (m,1H), 4.58 (m, 1H), 3.60 (m, 7H), 1.90 (m, 2H); LCMS: purity: 95%; MS(m/e): 456 (MH⁺). 7.4.352(±)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine(R908951) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-5-fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-4-pyrimidineamineand 3-chloro-4-methoxyaniline were reacted to yield(±)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.04 (d, 1H), 7.80 (m, 1H), 7.41 (m, 1H), 7.20 (m,2H), 6.97 (m, 2H), 4.61 (m, 1H), 3.73 (s, 3H), 3.50 (m, 2H), 1.90 (m,2H); LCMS: purity: 93%; MS (m/e): 460 (MH⁺). 7.4.353(S,S)-N2,N4-Bis-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R908952) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(S)-2-chloro-5-fluoro-N4-(2-methyl3-oxo-4H-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand (S)-6-amino-2-methyl-4H-benz[1,4]oxazine were reacted to yield(S,S)-N2,N4-bis-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.04 (d, 1H), 7.23 (m, 2H), 7.15 (m, 1H), 7.04 (m,1H), 6.92 (m, 2H), 4.58 (m, 2H), 1.38 (m, 6H); LCMS: purity: 95%; MS(m/e): 451 (MH⁺). 7.4.354(S)-N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R908953) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(S)-N2-chloro-5-fluoro-N4-(2-methyl-3-oxo-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 3,5-dimethoxyaniline were reacted to yield(S)-N2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.04 (d, 1H), 7.23 (m, 1H), 7.19 (m, 1H), 6.95 (m,3H), 6.05 (m, 1H), 4.61 (q, 1H), 3.60 (s, 6H), 1.40 (d, 3H); LCMS:purity: 98%; MS (m/e): 426 (MH⁺). 7.4.355(R)-N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine(R908954) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,(R)-N2-chloro-5-fluoro-N4-(2-methyl-3-oxo-benz[1,4]oxazin-6-yl)-4-pyrimidineamineand 3,5-dimethoxyaniline were reacted to yield(R)-N2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine¹HNMR (DMSO-d₆): δ8.04 (d, 1H), 7.23 (m, 1H), 7.19 (m, 1H), 6.95 (m, 3H),6.05 (m, 1H), 4.61 (q, 1H), 3.60 (s, 6H), 1.40 (d, 3H); LCMS: purity:98%; MS (m/e): 426 (MH⁺). 7.4.356N2-(3,5-Dichloro-4-methoxyphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine(R908955) In like manner to the synthesis ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-4-pyrimidineamineand 3,5-dichloro-4-methoxyaniline were reacted to yieldN2-(3,5-Dichloro-4-methoxyphenyl)-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.22 (d, 1H), 8.20 (d, 1H), 8.02 (dd, 1H), 7.62 (m,3H), 3.75 (s, 3H), 1.50 (s, 6H); LCMS: purity: 92%; MS (m/e): 491 (MH⁺).7.4.357N4-(4,4-Dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-N2-(indazol-6-yl)-5-fluoro-2,4-pyrimidinediamine (R908956) In like manner to thepreparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-N4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro-4-pyrimidineamineand 6-aminoindazole were reacted to yieldN4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-N2-(indazol-6-yl)-5-fluoro-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ8.28 (m, 2H), 8.17(m, 2H), 8.05 (m, 2H), 7.95 (s, 1H), 7.62 (m, 3H), 7.23 (m, 1H), 1.48(s, 6H); LCMS: purity: 95%; MS (m/e): 432 (MH⁺). 7.4.358N4-(3,3-Dimethyl-4H-benz[1,4]oxazin-6-yl)-N2-(3,5-dimethylphenyl)--5-fluoro-2,4-pyrimidinediamine(R908586) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-N4-(3,3-dimethyl-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3,5-dimethylaniline were reacted to yieldN4-(3,3-dimethyl-4H-benz[1,4]oxazin-6-yl)-N2-(3,5-dimethylphenyl)--5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.02 (d, 1H), 7.21 (m, 2H), 6.80 (m, 1H), 6.77 (m,1H), 6.60 (m, 1H), 6.50 (m, 1H), 3.75 (s, 2H), 2.15 (s, 6H), 1.15 (s,6H); LCMS: purity: 95%; MS (m/e): 394 (MH⁺). 7.4.359N2-(3-Chloro-4-methoxyphenyl)-N4-(3,3-dimethyl-4H-benzo[1,4]xazin-6-yl)-5-fluoro-2,4-pyrimidinediamine(R908587) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-N4-(3,3-dimethyl-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 3-chloro-4-methoxyaniline were reacted to yieldN2-(3-chloro-4-methoxyphenyl)-N4-(3,3-dimethyl-4H-benzo[1,4]xazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.01 (d, 1H), 7.81 (m, 1H), 7.58 (m, 1H), 6.97 (m,1H), 6.80 (m, 2H), 6.60 (m, 1H), 3.77 (s, 3H), 3.74 (s, 2H), 1.15 (s,6H); LCMS: purity: 94%; MS (m/e): 430 (MH⁺). 7.4.360N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine(R908591) In like manner to preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-N4-(3,3-dimethyl-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-aminoindazole were reacted to yieldN4-(3,3-dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.19 (s, 1H), 8.03 (d, 1H), 7.91 (s, 1H), 7.58 (m,1H), 7.22 (m, 1H), 6.97 (m, 1H), 6.84 (m, 1H), 6.64 (m, 1H), 3.77 (s,2H), 1.15 (s, 6H); LCMS: purity: 92%; MS (m/e): 406 (MH⁺). 7.4.361N4-(3,3-Dimethyl-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(N1-methylindazol-6-yl)-2,4-pyrimidinediamine(R908592) In like manner to the preparartion ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,N2-chloro-N4-(3,3-dimethyl-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-amino-N1-methylindazole were reacted to yieldN4-(3,3-dimethyl-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(N1-methylindazol-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ8.16 (s, 1H), 8.08 (d, 1H), 7.90 (s, 1H), 7.22 (m,1H), 7.22 (m, 1H), 6.97 (m, 2H), 6.64 (m, 1H), 3.80 (s, 3H), 3.77 (s,2H), 1.15 (s, 6H); LCMS: purity: 93%; MS (m/e): 420 (MH⁺). 7.4.362(R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamineToluenesulfonic Acid Salt (R908580) In like manner to the preparation ofN2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediaminep-Toluenesulfonic Acid Salt, the reaction of(R)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediaminewith p-Toluenesulfonic acid monohydrate gave(R)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamineToluenesulfonic Acid Salt. Preparation of Aminoindazolines 7.4.3631-(2-Ethoxycarbonylethyl)-5-nitroindazoline and2-(2-ethoxycarbonylethyl)-5-nitroindazoline In like manner to thepreparation of 1-(methoxycarbonyl)methyl-5-nitroindazoline,1-(2-ethoxycarbonylethyl)-5-nitroindazoline was prepared by alkylationof 5-nitroindazoline with ethyl 3-bromopropionate in presence of K₂CO₃.The 1-(2-ethoxycarbonylethyl)-5-nitroindazoline (43%) with high Rf valueon the TLC in 30% EtOAcn-hexanes was collected by silica gel columnchromatographic purification. ¹H NMR (CDCl₃): δ8.70 (d, 1H, J=1.7 Hz),8.27 (dd, 1H, J=2.3 and 8.8 Hz), 8.20 (d, 1H, J=1.7 Hz), 7.59 (d, 1H,J=8.8 Hz), 4.70 (t, 2H, J=6.4 Hz), 4.07 (qt, 2H, J=7.0 Hz), 3.01 (t, 2H,J=6.4 Hz), 1.16 (t, 3H, J=7.0 Hz). The lower Rf value by-product,2-(2-ethoxycarbonylethyl)-5-nitroindazoline was also collected byeluting the column with 50% EtOAcn-hexanes. ¹H NMR (CDCl₃): δ8.71 (d.1H. J=2.0 Hz), 8.32 (s, 1H), 8.08 (app dd, 1H, J=2.0 and 9.7 Hz), 7.73(dd, 1H, J=0.8 and 9.7 Hz), 4.77 (t, 2H, J=6.4 Hz), 4.12 (qt, 2H, J=7.0Hz), 3.08 (t, 2H, J=6.4 Hz), 1.22 (t, 3H, J=7.0 Hz). 7.4.3645-Amino-1-(2-ethoxycarbonylethyl)indazoline In like manner to thereduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate,1-(2-ethoxycarbonylethyl)-5-nitroindazoline was reduced to provide5-amino-1-(2-ethoxycarbonylethyl)indazoline. ¹H NMR (CDCl₃): δ7.78 (s,1H), 7.30 (d, 1H, J=8.8 Hz), 6.91 (d, 1H, J=2.3 Hz), 6.87 (dd, 1H, J=2.3and 8.8 Hz), 4.59 (t, 2H, J=6.4 Hz), 4.08 (qt, 2H, J=7.0 Hz), 3.02 (brs, 2H), 2.92 (t, 2H, J=7.0 Hz), 1.16 (t, 3H, J=7.0 Hz). 7.4.3655-Amino-2-(2-ethoxycarbonylethyl)indazoline In like manner to thereduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, the reductionof 2-(2-ethoxycarbonylethyl)-5-nitroindazoline provided5-amino-2-(2-ethoxycarbonylethyl)indazoline. ¹H NMR (CDCl₃): δ7.64 (s,1H), 7.45 (dd, 1H, J=0.9 and 9.1 Hz), 6.74 (dd, 1H, J=2.0 and 9.1 Hz),6.67(d, 1H, J=2.0 Hz), 4.57 (t, 2H, J=6.7 Hz), 4.05 (qt, 2H, J=7.0 Hz),3.28 (br s, 2H), 2.93 (t, 2H, J=6.7 Hz), 1.16 (t, 3H, J=7.0 Hz). 7.4.3661-methyl-6-nitroindazoline and 2-methyl-6-nitroindazoline In like mannerto the preparation of 1-(methoxycarbonylmethyl)-5-nitroindazoline,6-nitroindazole was alkylated with methyl iodide in presence of K₂CO₃.The reaction mixture was diluted with water upon completion of thereaction. The solid formed was filtered, dried and chromatographed with15% EtOAc:n-n-hexanes on silica gel to provide high Rf value product1-methyl-6-nitroindazoline . ¹H NMR (CDCl₃): δ8.32 (s, 1H), 8.10 (s,1H), 8.01 (dd, 1H, J=2.7 and 8.8 Hz), 7.83 (d, 1H, J=8.8 Hz), 4.18 (s,3H). The lower Rf value by-product 2-methyl-6-nitroindazoline was alsocollected by eluting the column with 30% EtOAc:n-hexanes. ¹H NMR(CDCl₃): δ8.69 (d, 1H, J=2.0 Hz), 8.03 (s, 1H), 7.90 (dd, 1H, J=2.0 and9.1 Hz), 7.75 (d, 1H, J=9.1 Hz), 4.31 (s, 13H). 7.4.3676-Amino-1-methylindazoline In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate, 1-methyl-6-nitroindazoline wasreduced to give 6-amino-1-methylindazoline. ¹H NMR (CDCl₃): δ7.80 (s,1H), 7.48 (dd, 1H, J=0.6 and 8.2 Hz), 6.58 (dd, 1H, J=1.8 and 8.2 Hz),6.54 (d, 1H, J=0.6 Hz), 3.94 (s, 3H), 3.5 (br s, 2H). 7.4.3686-Amino-2-methylindazoline In like manner to the reduction of diethyl2-methyl-2-(3-nitrophenoxy)malonate, 2-methyl-6-nitroindazoline wasreduced to give 6-amino-2-methylindazoline. ¹H NMR (CDCl₃): δ7.71 (s,1H), 7.43 (d, 1H, J=8.8 Hz), 6.79 (app d, 1H, J=1.7 Hz), 6.58 (dd, 1H,J=1.7 and 8.8 Hz), 4.11 (s, 3H), 3.31 (br s, 2H). 7.4.3692-Chloro-5-fluoro-N4-(4-fluoro-3-methoxyphenyl)-4-pyrimidineamine Inlike manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-methoxyaniline werereacted to provide2-chloro-5-fluoro-N4-(4-fluoro-3-methoxyphenyl)-4-pyrimidineamine . ¹HNMR (DMSO-d₆): δ9.99 (s, 1H), 8.31 (d, 1H, J=3.5 Hz), 7.54 (dd, 1H,J=8.2 Hz), 7.30-7.17 (m, 2H), 3.81 (s, 3H). LCMS: ret. time: 12.11 min.;purity: 98%; MS (m/e): 272 (MH⁺). 7.4.3702-Chloro-N4-(4-chloro-3-fluorophenyl)-5-fluoro-4-pyrimidineamine In likemanner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-fluoroaniline werereacted to provide2-chloro-N4-(4-chloro-3-fluorophenyl)-5-fluoro-4-pyrimidineamine. ¹H NMR(DMSO-d₆): δ10.25 (s, 1H), 8.39 (d, 1H, J=3.5 Hz), 7.87 (dd, 1H, J=1.8and 11.4 Hz), 7.59 (m, 1H), 7.09-6.38 (m, 1H). LCMS: ret. time: 13.74min.; purity: 93%; MS (m/e): 277 (MH⁺). 7.4.3712-Chloro-N4-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidineamine In likemanner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline werereacted to provide2-chloro-N4-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidineamine. ¹H NMR(DMSO-d₆): δ10.12 (s, 1H), 8.35 (s, 1H), 7.93 (dd, 1H, J=2.6 and 7.6Hz), 7.69-7.64 (m, 1H), 7.43 (t, 1H, J=9.2 Hz). LCMS: ret. time: 13.38min.; purity: 91%; MS (m/e): 277 (MH⁺). 7.4.372N4-(2,6-Dimethoxypyrid-3-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935381) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(2,6-dimethoxypyrid-3-yl)-5-fluoro-4-pyrimidineamine and5-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(2,6-dimethoxypyrid-3-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.08 (s, 1H), 8.68 (s, 1H), 8.00 (d, 1H, J=4.1 Hz),7.93 (s, 1H), 7.74 (d, 1H, J=8.2 Hz), 7.67 (s, 1H), 7.42 (d, 1H, J=9.4Hz), 7.34 (d, 1H, J=9.4 Hz), 6.46 (d, 1H, J=8.2 Hz), 4.51 (t, 2H, J=6.4Hz), 3.96 (qt, 2H, J=7.0 Hz), 3.91 (s, 1H), 3.83 (s, 1H), 2.85 (t, 2H,J=6.4 Hz), 1.05 (t, 3H, J=7.0 Hz). LCMS: ret. time: 10.94 min.; purity:90%; MS (m/e): 482 (MH⁺). 7.4.373N4-(4-Chlorophenyl)-5-fluoro-N2-{1-[2-(N-methylamino)carbonylethyl]indazolin-5-yl}-2,4-pyrimidinediamine(R935382) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(4-chlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt were reacted to provideN4-(4-chlorophenyl)-5-fluoro-N2-{1-[2-(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.44 (s, 1H), 9.21 (s, 1H), 8.11 (d, 1H, J=4.1 Hz),8.07 (s, 1H), 7.85 (d, 2H, J=9.4 Hz), 7.82 (dd, 2H, J=2.9 and 8.8 Hz),7.52 (d, 1H, J=9.4 Hz), 7.46 (d, 1H, J=8.2 Hz), 7.34 (d, 1H, J=8.8 Hz),4.53 (t, 2H, J=7.0 Hz), 2.63 (t, 2H, J=7.0 Hz), 2.49 (d, 3H, J=4.7 Hz).LCMS: ret. time: 8.58 min.; purity: 97%; MS (m/e): 440 (MH⁺). 7.4.374N4-(4-Chlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine(R935383) In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(4-chlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with diisobutyl lithiumaluminum hydride to produceN4-(4-chlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.44 (s, 1H), 9.20 (s, 1H), 8.11 (d, 1H, J=4.2 Hz),8.07 (s, 1H), 7.85 (d, 1H, J=9.4 Hz), 7.82 (dd, 2H, J=2.9 and 8.8 Hz),7.52 (d, 1H, J=9.4 Hz), 7.46 (d, 1H, J=9.4 Hz), 7.32 (d, 1H, J=8.8 Hz),4.56 (t, 1H, J=5.2 Hz), 4.39 (t, 2H, J=6.4 Hz), 3.35 (app q, 2H, J=6.4Hz), 1.93 (q, 2H, J=6.4 Hz). LCMS: ret. time: 8.85 min.; purity: 96%; MS(m/e): 413 (MH⁺). 7.4.375N4-(3,4-Difluorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935384) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine and5-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(3,4-difluorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.30 (s, 1H), 10.09 (s, 1H), 8.26 (d, 1H, J=4.7 Hz),7.95 (s, 1H), 7.89 (s, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.47-7.32 (m, 3H),4.60 (t, 2H, J=6.4 Hz), 3.97 (qt, 2H, J=7.0 Hz), 2.90 (t, 2H, J=6.4 Hz),1.06 (t, 3H, J=7.0 Hz). LCMS: ret. time: 11.45 min.; purity: 96%; MS(m/e): 457 (MH⁺). 7.4.376N4-(3,4-Difluorophenyl)-5-fluoro-N2-{1-[2-(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine(R935385) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-difluorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt were reacted to provideN4-(3,4-difluorophenyl)-5-fluoro-N2-{1-[2(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.49 (s, 1H), 9.27 (s, 1H), 8.13 (d, 1H, J=3.5 Hz),8.08-8.00 (app s, 2H), 2.87 (s, 1H), 7.83 (qt, 1H, J=4.7 Hz), 7.56-7.49(m, 3H), 7.36 (dd, 1H, J=8.8 and 20.1 Hz), 4.52 (t, 2H, J=6.4 Hz), 2.63(t, 2H, J=6.4 Hz), 2.59 (d, 3H, J=4.7 Hz). LCMS: ret. time: 8.44 min.;purity: 96%; MS (m/e): 442 (MH⁺). 7.4.377N4-(3,4-Difluorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine(R935386) In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3,4-difluorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with diisobutyl lithiumaluminum hydride to produceN4-(3,4-difluorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.49 (s, 1H), 9.26 (s, 1H), 8.13 (d, 1H, J=3.5 Hz),8.07-8.03 (app s, 2H), 7.86 (s, 1H), 7.54-7.45 (m, 3H), 7.33 (dd, 1H,J=8.8 and 19.3 Hz), 4.56 (t, 1H, J=4.7 Hz), 4.39 (t, 2H, J=6.5 Hz), 3.35(qt, 2H, J=6.5 Hz), 1.93 (q, 2H, J=6.5 Hz). LCMS: ret. time: 8.86 min.;purity: 96%; MS (m/e): 415 (MH⁺). 7.4.378N4-(3,4-Dichlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935389) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and5-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(3,4-dichlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.25 (s, 1H), 10.00 (s, 1H), 8.27 (d, 1H, J=4.7 Hz),8.02 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.72 (d, 1H, J=8.8 Hz), 7.65(d, 1H, J=8.8 Hz), 7.52 (d, 1H, J=8.8 Hz), 7.35 (d, 1H, J=8.8 Hz), 4.59(t, 2H, J=6.4 Hz), 3.97 (qt, 2H, J=7.0 Hz), 2.90 (t, 2H, J=6.4 Hz), 1.06(t, 3H, J=7.0 Hz). LCMS: ret. time: 13.10 min.; purity: 95%; MS (m/e):490 (MH⁺). 7.4.379N4-(3,4-Dichlorophenyl)-5-fluoro-N2-{1-[2(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine(R935390) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-dichlororophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt were reacted to provideN4-(3,4-dichlorophenyl)-5-fluoro-N2-{1-[2(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.55 (s, 1H), 9.28 (s, 1H), 8.15 (d, 1H, J=3.5 Hz),8.08 (d, 1H, J=2.3 Hz), 8.00 (s, 1H), 7.86 (s, 1H), 7.80 (m, 2H),7.55-7.44 (m, 3H), 4.52 (t, 2H, J=7.0 Hz), 2.63 (t, 2H, J=7.0 Hz), 2.50(d, 3H, J=4.7 Hz). LCMS: ret. time: 9.83 min.; purity: 96%; MS (m/e):475 (MH⁺). 7.4.380N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine(R935391) In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3,4-dichlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with diisobutyl lithiumaluminum hydride to produceN4-(3,4-dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.67 (s, 1H), 9.38 (s, 1H), 8.23 (d, 1H, J=3.5 Hz),8.17 (app t, 1H, J=2.3 Hz), 8.08 (s, 1H), 7.95 (s, 1H), 7.87 (d, 1H,J=8.8 Hz), 7.62 (d, 1H, J=8.8 Hz), 7.59 -7.53 (m, 2H), 4.47 (t, 2H,J=6.4 Hz), 3.44 (app t , 2H, J=6.4 Hz), 2.02 (q, 2H, J=6.4 Hz). LCMS:ret. time: 10.31 min.; purity: 95%; MS (m/e): 448 (MH⁺). 7.4.381N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935392) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and1-methyl-6-aminoindazole were reacted to giveN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.40 (s, 1H), 10.27 (s, 1H), 8.27 (d, 1H, J=4.7 Hz),7.95 (s, 1H), 7.81 (s, 1H), 7.66 (d, 1H, J=8.8 Hz), 7.25-7.23 (m, 1H),7.15-7.09 (m, 2H), 6.77 (d, 1H, J=8.8 Hz), 4.24-4.15 (m, 4H), 3.81 (s,3H). LCMS: ret. time: 9.19 min.; purity: 97%; MS (m/e): 393 (MH⁺).7.4.382N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935393) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and1-methyl-6-aminoindazole were reacted to giveN4-(3,4-dichlorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.68 (s, 1H), 9.56 (s, 1H), 8.23 (d, 1H, J=4.1 Hz),8.13 (d, 1H, J=2.3 Hz), 7.98 (s, 1H), 7.86 (s, 1H), 7.79 (dd, 1H, J=2.3and 8,8 Hz), 7.58 (d, 1H, J=8.8 Hz), 7.53 (d, 1H, J=8.8 Hz), 7.22 (dd,1H, J=2.3 and 8.8 Hz), 3.77 (s, 3H). LCMS: ret. time: 13.48 min.;purity: 97%; MS (m/e): 404 (MH⁺). 7.4.3832-Chloro-5-fluoro-N-(1-methylindazolin-6-yl)-4-pyrimidineamine (R935394)In like manner to the preparation of2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine,2,4-dichloro-5-fluoropyrimidine and 6-amino-1-methyl-indazoline werereacted to provide2-chloro-5-fluoro-N-(1-methylindazolin-6-yl)-4-pyrimidineamine. ¹H NMR(DMSO-d₆): δ10.15 (s, 1H), 8.34 (d, 1H, J=3.5 Hz), 8.00 (s, 1H), 7.98(app s, 1H), 7.72 (d, 1H, J=8.2 Hz), 7.39 (d, 1H, J=8.2 Hz), 3.81 (s,3H). LCMS: ret. time: 10.45 min.; purity: 95%; MS (m/e): 278 (MH⁺).7.4.384N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935395) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methylindazolin-6-yl)-4-pyrimidineamine wasreacted with 4-amino-2-chloro-6-methylphenol to giveN2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.48 (s, 1H), 9.06 (s, 1H), 8.58 (s, 1H), 8.11 (d,1H, J=3.5 Hz), 8.07 (s, 1H), 7.93 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.56(s, 1H), 7.36 (dd, 1H, J=2.3 and 8.8 Hz), 7.21 (d, 1H, J=2.3 Hz), 3.87(s, 3H), 1.99 (s, 3H). LCMS: ret. time: 9.13 min.; purity: 95%; MS(m/e): 399 (MH⁺). 7.4.385N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[2-(2-methoxy-4-methoxycarbonylbenzyl)indazolin-6-yl]-2,4-pyrimidinediamine (R935396) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine was reactedwith 6-amino-2-(2-methoxy-4-methoxycarbonylbenzyl)indazoline to provideN4-(3,4-dichlorophenyl)-5-fluoro-N2-[2-(2-methoxy-4-methoxycarbonylbenzyl)indazolin-6-yl]-2,4-pyrimidinediamine.LCMS: ret. time: 14.80 min.; purity: 94%; MS (m/e): 568 (MH⁺). 7.4.386N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(2-methoxy-4-methoxycarbonylbenzyl)indazolin-6-yl]-2,4-pyrimidinediamine (R935398) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine wasreacted with 6-amino-2-(2-methoxy-3-methoxycarbonylbenzyl)indazoline toprovideN4-(3,4-dichlorophenyl)-5-fluoro-N2-[2-(2-methoxy-4-methoxycarbonylbenzyl)indazolin-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.80 (s, 1H), 9.66 (s, 1H), 8.32 (s, 1H), 8.16 (d,1H, J=4.4 Hz), 7.90 (s, 1H), 7.71 (d, 2H, J=3.5 Hz), 7.61 (d, 1H, J=8.2Hz), 7.52 (s, 1H), 7.49 (d, 1H, J=8.2 Hz), 7.15 (d, 1H, J=8.5 Hz), 7.09(d, 1H, J=8.5 Hz), 6.89 (d, 1H, J=8.5 Hz), 5.59 (s, 2H), 3.91 (s, 3H),3.83 (s, 3H), 3.77 (s, 3H). LCMS: ret. time: 12.16 min.; purity: 94%; MS(m/e): 563 (MH⁺). 7.4.387N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-{1-[2-methoxy-4-(N-methylaminocarbonyl)benzyl]indazolin-6-yl}-2,4-pyrimidinediamine(R935399) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-methoxy-4-methoxycarbonylbenzyl)indazolin-6-yl]-2,4-pyrimidinediamineand methylamine hydrochloride salt were reacted to provideN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-{1-[2-methoxy-4-(N-methylaminocarbonyl)benzyl]indazolin-6-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.15 (s, 1H), 8.42 (qt, 1H, J=3.5 Hz), 8.20 (s, 1H),8.06 (d, 1H, J=3.3 Hz), 8.05 (s, 1H), 7.50 (d, 1H, J=8.8 Hz), 7.45 (s,1H), 7.34 (dd, 1H, J=1.2 and 7.6 Hz), 7.28-7.26 (m, 2H), 7.18 (dd, 1H,J=2.3 and 8.3 Hz), 6.93 (d, 1H, J=7.6 Hz), 6.77 (dd, 1H, J=2.3 and 8.8Hz), 5.52 (s, 2H), 4.18 (s, 4H), 3.88 (s, 3H), 2.76 (d, 3H, J=3.5 Hz).LCMS: ret. time: 9.03 min.; purity: 91%; MS (m/e): 556 (MH⁺). 7.4.388N4-(3,4-Difluorophenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine(R935400) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-difluorophenyl)-5-fluoro 4-pyrimidineamine and6-aminoindazoline were reacted to giveN4-(3,4-difluorophenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.66 (s, 1H), 9.56 (s, 1H), 8.20 (d, 1H, J=4.1 Hz),8.16-8.05 (m, 2H), 7.91 (s, 1H), 7.59 (d, 2H, J=8.8 Hz), 7.36 (dd, 1H,J=19.9 and 8.8 Hz), 7.24 (dd, 1H, J=1.7 and 8.8 Hz). LCMS: ret. time:10.39 min.; purity: 94%; MS (m/e): 357 (MH⁺). 7.4.389N4-(3,4-Difluorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935401) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine and1-methyl-6-aminoindazole were reacted to giveN4-(3,4-difluorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.15 (s, 1H), 10.09 (s, 1H), 8.29 (d, 1H, J=4.1 Hz),8.03-7.97 (m, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.65 (d, 1H, J=8.8 Hz),7.50-7.52 (m, 1H), 7.37 (dd, 1H, J=8.3 and 19.4 Hz), 7.21 (d, 1H, J=8.3Hz), 3.84 (s, 3H). LCMS: ret. time: 11.78 min.; purity: 98%; MS (m/e):371 (MH⁺). 7.4.390N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935402) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and1-methyl-6-aminoindazole were reacted to giveN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.43 (s, 1H), 9.37 (s, 1H), 8.14 (d, 1H, J=3.5 Hz),7.99 (s, 1H), 7.83-7.81 (m, 2H), 7.69-7.65 (m, 1H), 7.54 (d, 1H, J=8.8Hz), 7.21 (d, 1H, J=8.2Hz), 7.11 (d, 1H, J=8.8 Hz), 3.82 (s, 3H), 3.72(s, 3H). LCMS: ret. time: 10.60 min.; purity: 94%; MS (m/e): 399 (MH⁺).7.4.391N4-(3,4-Dichlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamine(R935403) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and6-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(3,4-dichlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.65 (s, 1H), 9.53 (s, 1H), 8.22 (d, 1H, J=3.5 Hz),8.12 (t, 1H, J=2.9 Hz), 8.00 (s, 1H), 7.90 (s, 1H), 7.82 (app dd, 1H,J=2.9 and 8.8 Hz), 7.57 (d, 1H, J=8.8 Hz), 7.53 (d, 1H, J=8.8 Hz), 7.28(d, 1H, J=8.8 Hz), 4.34 (t, 2H, J=6.4 Hz), 3.94 (qt, 2H, J=7.0 Hz), 2.83(t, 2H, J=6.4 Hz), 1.04 (t, 3H, J=7.0 Hz). LCMS: ret. time: 14.36 min.;purity: 99%; MS (m/e): 490 (MH⁺). 7.4.392N4-(3,4-Dichlorophenyl)-5-fluoro-N2-{1-[2(N-methylamino)carbonylethyl]indazolin-6-yl}-2,4-pyrimidinediamine(R935404) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-dichlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt were reacted to provideN4-(3,4-dichlorophenyl)-5-fluoro-N2-{1-[2(N-methylamino)carbonylethyl]indazolin-6-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.64 (s, 1H), 9.51 (s, 1H), 8.22 (d, 1H, J=3.5 Hz),8.13 (t, 1H, J=2.9 Hz), 7.95 (s, 1H), 7.89 (s, 1H), 7.85-7.79 (m, 2H),7.58 (d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=8.8 Hz), 7.29 (d, 1H, J=8.8 Hz),4.33 (t, 2H, J=6.4 Hz), 2.60 (t, 2H, J=6.4 Hz), 2.48 (d, 3H, J=3.5 Hz).LCMS: ret. time: 11.09 min.; purity: 95%; MS (m/e): 475 (MH⁺). 7.4.393N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-6-yl]-2,4-pyrimidinediamine(R935405) In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3,4-dichlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with diisobutyl lithiumaluminum hydride to produceN4-(3,4-dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.72 (s, 1H), 9.59 (s, 1H), 8.29 (d, 1H, J =3.5 Hz),8.20 (t, 1H, J=2.9 Hz), 8.02 (s, 1H), 7.96 (s, 1H), 7.90 (d, 1H, J=8.8Hz), 7.66 (d, 1H, J=8.8 Hz), 7.61 (d, 1H, J=8.8 Hz), 7.38 (d, 1H, J=8.8Hz), 4.58 (t, 1H, J=4.7 Hz), 4.26 (app t, 2H, J=6.4 Hz), 3.36 (app t,2H, J=7.0 Hz), 1.94 (q, 2H, J=6.4 Hz). LCMS: ret. time: 11.84 min.;purity: 94%; MS (m/e): 448 (MH⁺). 7.4.394N4-(3-Chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamine(R935406) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and6-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(3-chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.41 (s, 1H), 9.36 (s, 1H), 8.14 (d, 1H, J=3.5 Hz),8.01 (s, 1H), 7.87 (s, 1H), 7.83 (t, 1H, J=2.9 Hz), 7.71-7.66 (m, 1H),7.54 (d, 1H, J=8.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, J=8.8 Hz),4.28 (t, 2H, J=6.4 Hz), 3.93 (qt, 2H, J=7.0 Hz), 3.82 (s, 3H), 2.80 (t,2H, J=6.4 Hz), 1.03 (t, 3H, J=7.0 Hz). LCMS: ret. time: 11.77 min.;purity: 98%; MS (m/e): 486 (MH⁺). 7.4.395N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-6-yl]-2,4-pyrimidinediamine(R935407) In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with diisobutyl lithiumaluminum hydride to produceN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-6-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.38 (s, 1H), 9.35 (s, 1H), 8.13 (d, 1H, J=3.5 Hz),7.95 (s, 1H), 7.85 (s, 1H), 7.84 (app t, 1H, J=2.9 Hz), 7.70-7.65 (m,1H), 7.55 (d, 1H, J=8.8 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, J=8.8Hz), 4.48 (t, 1H, J=5.3 Hz), 4.13 (t, 2H, J=7.0 Hz), 3.82 (s, 3H), 3.26(t, 2H, J=7.0 Hz), 1.83 (app q, 2H, J=7.0 Hz). LCMS: ret. time: 9.34min.; purity: 97%; MS (m/e): 443 (MH⁺). 7.4.396N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine(R935408) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and6-aminoindazoline were reacted to giveN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.64 (s, 1H), 9.27 (s, 2H), 8.08 (d, 1H, J=3.5 Hz),7.98 (s, 1H), 7.83 (s, 1H), 7.80 (d, 1H, J=2.9 Hz), 7.73 (dd, 1H, J=2.9and 8.8 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.25 (d, 1H, J=8.8 Hz), 7.04 (d,1H, J=8.8 Hz), 3.78 (s, 3H). LCMS: ret. time: 9.46 min.; purity: 92%; MS(m/e): 385 (MH⁺). 7.4.397N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-{1-[2-(N-methylaminocarbonyl)ethyl]indazolin-6-yl}-2,4-pyrimidinediamine(R935409) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamineand hydrogen chloride salt were reacted to provideN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-{1-[2(N-methylaminocarbonyl)ethyl]indazolin-6-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.39 (s, 1H), 9.35 (s, 1H), 8.14 (d, 1H, J=3.5 Hz),7.96 (s, 1H), 7.86 (d, 1H, J=1.2 Hz), 7.83 (d, 1H, J=2.3 Hz), 7.79 (qt,1H, J=4.7 Hz), 7.68 (dd, 1H, J=2.3 and 8.8 Hz), 7.54 (d, 1H, J=8.8 Hz),4.28 (t, 2H, J=7.0 Hz), 3.82 (s, 3H), 3.30 (d, 3H, J=4.7 Hz), 2.56 (t,2H, J=7.0 Hz). LCMS: ret. time: 8.98 min.; purity: 93%; MS (m/e): 471(MH⁺). 7.4.3985-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine(R935410) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-fluoro-3-methoxyphenyl)-4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to give5-fluoro-N4-(4-fluoro-3-methoxyphenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.32 (s, 1H), 9.18 (s, 1H), 8.12-8.11 (m, 1H), 8.09(d, 1H, J=3.5 Hz), 7.79 (app d, 1H, J=1.8 Hz), 7.51-7.47 (m, 3H),7.37-7.32 (m, 1H), 7.13 (dd, 1H, J=8.8 and 11.1 Hz), 3.98 (s, 3H), 3.68(s, 3H). LCMS: ret. time: 9.18 min.; purity: 98%; MS (m/e): 383 (MH⁺).7.4.399N4-(4-Chloro-3-fluorophenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine(R935411) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chloro-3-fluorophenyl)-5-fluoro-4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to giveN4-(4-chloro-3-fluorophenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.60 (s, 1H), 9.31 (s, 1H), 8.16 (d, 1H, J=3.5 Hz),8.13-8.11 (m, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.60-7.54 (m, 1H),7.51-7.42 (m, 3H), 3.99 (s, 3H). LCMS: ret. time: 9.87 min.; purity:100%; MS (m/e): 387 (MH⁺). 7.4.400N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine(R935412) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3, 4-dimethoxyphenyl)-5-fluoro 4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to giveN4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.21 (s, 1H), 10.12 (s, 1H), 8.18 (d, 1H, J=5.3 Hz),7.96 (s, 1H), 7.85 (s, 1H), 7.57 (d, 1H, J=8.8 Hz), 7.36 (d, 1H, J=8.8Hz), 7.23-7.17 (m, 2H), 6.89 (d, 1H. J=8.8 Hz), 4.00 (s, 3H), 3.75 (s,3H), 3.57 (s, 3H). LCMS: ret. time: 7.80 min.; purity: 99%; MS (m/e):395 (MH⁺). 7.4.401N2-(3-Chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4-(indazolin-6-yl)-2,4-pyrimidinediamine(R93413) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazolin-6-yl)-4-pyrimidineamine was reacted with3-chloro-4-methoxy-5-methylaniline to produceN2-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.88 (s, 1H), 9.48 (s, 1H), 9.25 (s, 1H), 8.13 (d,1H, J=3.5 Hz), 7.98 (s, 1H), 7.79 (s, 1H), 7.69 (d, 1H, J=8.8 Hz), 7.63(d, 1H, J=2.3 Hz), 7.45 (dd, 1H, J=1.9 and 8.8 Hz), 7.42 (d, 1H, J=2.3Hz), 3.63 (s, 3H), 2.01 (s, 3H). LCMS: ret. time: 10.87 min.; purity:95%; MS (m/e): 399 (MH⁺). 7.4.402N4-(4-Chloro-3-fluorophenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine(R935414) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chloro-3-fluorophenyl)-5-fluoro 4-pyrimidineamine and6-aminoindazoline were reacted to giveN4-(4-chloro-3-fluorophenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.71 (s, 1H), 9.55 (s, 1H), 8.20 (t, 1H, J=2.3 Hz),8.22 (d, 1H, J=3.5 Hz), 8.16 (app d, 1H, J=2.3 Hz), 8.07 (s, 1H), 7.91(s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.59 (d, 1H, J=8.8 Hz), 7.47 (t, 1H,J=8.8 Hz), 7.25 (dd, 1H, J=1.8 and 8.8 Hz). LCMS: ret. time: 9.02 min.;purity: 100%; MS (m/e): 373 (MH⁺). 7.4.403N4-(4-Chloro-3-fluorophenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidinediamine(R935415) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(4-chloro-3-fluorophenyl)-5-fluoro 4-pyrimidineamine and5-aminoindazoline were reacted to giveN4-(4-chloro-3-fluorophenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.36 (s, 1H), 10.09 (s, 1H), 8.27 (d, 1H, J=4.7 Hz),7.97 (s, 1H), 7.95 (s, 1H), 7.90 (s, 1H), 7.52 (d, 1H, J=8.8 Hz), 7.50(d, 1H, J=8.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.39 (dd, 1H, J=1.8 and 8.8Hz). LCMS: ret. time: 9.87 min.; purity: 100%; MS (m/e): 387 (MH⁺).7.4.4045-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(indazolin-6-yl)-2,4-pyrimidinediamine(R935416) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-fluoro-3-methoxyphenyl)-4-pyrimidineamine and6-aminoindazoline were reacted to give5-fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.70 (s, 1H), 9.35 (s, 1H), 9.32 (s, 1H), 8.14 (d,1H, J=4.1 Hz), 8.07 (s, 1H), 7.88 (s, 1H), 7.54 (dd, 1H, J=3.5 and 8.8Hz), 7.50-7.46 (m, 2H), 7.26 (dd, 1H, J=1.2 and 8.2 Hz), 7.11 (dd, 1H,J=8.8 and 11.8 Hz), 3.72 (s, 3H). LCMS: ret. time: 9.34 min.; purity:93%; MS (m/e): 369 (MH⁺). 7.4.4055-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(indazolin-5-yl)-2,4-pyrimidinediamine(R935417) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-fluoro-3-methoxyphenyl)-4-pyrimidineamine and5-aminoindazoline were reacted to give5-fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(indazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.84 (s, 1H), 9.33 (s, 1H), 9.16 (s, 1H), 8.09 (d,1H, J=3.5 Hz), 7.83 (s, 1H), 7.49 (dd, 1H, J=2.3 and 8.3 Hz), 7.43 (dd,1H, J=2.3 and 8.3 Hz), 7.37 (d, 1H, J=8.8 Hz), 7.35-7.30 (m, 2H), 7.11(dd, 1H, J=8.8 and 11.1 Hz), 3.67 (s, 3H). LCMS: ret. time: 8.09 min.;purity: 97%; MS (m/e): 369 (MH⁺). 7.4.406N2-(3-Chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4-{4H-imidazo[2,1-c]-benz[1,4]oxazin-8-yl}-2,4-pyrimidinediamine(R935418) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-{4H-imidazo[2,1-c]-benz[1,4]oxazin-8-yl}-4-pyrimidineaminewas reacted with 3-chloro-4-methoxy-5-methylaniline to produceN2-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4-{4H-imidazo[2,1-c]-benz[1,4]oxazin-8-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.48 (s, 1H), 9.27 (s, 1H), 8.11 (d, 1H, J=3.5 Hz),7.99 (d, 1H, J=2.3 Hz), 7.71 (s, 1H), 7.64 (d, 1H, J=2.3 Hz), 7.35 (dd,1H, J=2.3 and 8.8 Hz), 7.31 (d, 1H, J=2.3 Hz), 7.13 (d, 2H, J=8.8 Hz),5.26 (s, 2H), 3.58 (s, 3H), 2.01 (s, 3H). LCMS: ret. time: 10.68 min.;purity: 95%; MS (m/e): 453 (MH⁺). 7.4.407N2-(3-Chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935419) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methylindazolin-6-yl)-4-pyrimidineamine wasreacted with 3-chloro-4-methoxy-5-methylaniline to giveN2-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.17 (s, 1H), 9.87 (s, 1H), 8.25 (d, 1H, J=3.7 Hz),7.99 (s, 1H), 7.96 (s, 1H), 7.71 (d, 1H, J=8.2 Hz), 7.58 (t, 1H, J=2.3Hz), 7.37 -7.33 (m, 1H), 7.26 (s, 1H), 3.89 (s, 3H), 3.64 (s, 3H), 2.02(s, 3H); LCMS: ret. time: 12.15 min.; purity: 98%; MS (m/e): 413 (MH⁺).7.4.408 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935420) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methylindazolin-6-yl)-4-pyrimidineamine wasreacted with 3,5-dimethoxyaniline to giveN2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.67 (s, 1H), 10.44 (s, 1H), 8.36 (d, 1H, J=4.9 Hz),8.01 (s, 2H), 7.72 (d, 1H, J=8.8 Hz), 7.32 (d, 1H, J=8.8 Hz), 6.70 (s,2H), 6.21 (s, 1H), 3.87 (s, 3H), 3.52 (s, 6H). LCMS: ret. time: 10.75min.; purity: 100%; MS (m/e): 395 (MH⁺). 7.4.409N2-(4-Chloro-2,5-dimethoxyphenyl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935421) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methylindazolin-6-yl)-4-pyrimidineamine wasreacted with 4-chloro-2,5-dimethoxyaniline to giveN2-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.56 (s, 2H), 8.13 (d, 1H, J=4.5 Hz), 8.05 (s, 1H),7.92 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.62 (d, 1H, J=8.8 Hz), 7.31 (dd,1H, J=5.0 and 8.8 Hz), 7.06 (s, 1H), 3.88 (s, 3H), 3.78 (s, 3H), 3.30(s, 3H). LCMS: ret. time: 12.81 min.; purity: 100%; MS (m/e): 429 (MH⁺).7.4.410N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(indazolin-6-yl)-2,4-pyrimidinediamine(R935423) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazolin-6-yl)-4-pyrimidineamine was reacted with3,5-dimethoxyaniline to produceN2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.52 (s, 1H), 10.26 (s, 1H), 8.30 (d, 1H, J=5.3 Hz),8.03 (s, 1H), 7.57 (s, 1H), 7.69 (d, 1H, J=8.8 Hz), 7.42-7.37 (m, 1H),6.68 (d, 2H, J=2.3 Hz), 6.15 (d, 1H, J=2.3 Hz), 3.49 (s, 6H). LCMS: ret.time: 9.23 min.; purity: 100%; MS (m/e): 381 (MH⁺). 7.4.411N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazine-6-yl)-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935424) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methylindazolin-6-yl)-4-pyrimidineamine wasreacted with 6-amine-2,2-dimethyl-3-oxo-4H-benz[1,4]oxazine to giveN2-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N4-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.65 (s, 1H), 8.20 (d, 1H, J=4.7 Hz), 8.06 (s, 1H),7.97 (s, 1H), 7.67 (d, 1H, J=8.5 Hz), 7.43-7.38 (m, 1H), 7.13 (d, 1H,J=8.8 Hz), 7.00 (s, 1H), 6.78 (d, 1H, J=8.8 Hz), 3.91 (s, 3H), 1.36 (s,6H). LCMS: ret. time: 9.20 min.; purity: 100%; MS (m/e): 434 (MH⁺).7.4.412N4-(3-Chloro-4-fluorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935425) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidineamime and1-methyl-6-aminoindazoline were reacted to giveN4-(3-chloro-4-fluorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.57 (s, 1H), 9.51 (s, 1H), 8.21 (d, 1H, J=3.5 Hz),8.06 (d, 1H, J=4.1 Hz), 7.98 (s, 1H), 7.86 (d, 1H, J=0.7 Hz), 7.78-7.75(m, 1H), 7.57 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=9.0 and 8.8 Hz), 7.24(td, 1H, J=1.4, 9.0 and 8.8 Hz), 3.79 (s, 3H). LCMS: ret. time: 12.34min.; purity: 97%; MS (m/e): 387 (MH⁺). 7.4.413N4-(3-Chloro-4-fluorophenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine(R935426) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidineamime and1-methyl-5-aminoindazoline were reacted to giveN4-(3-chloro-4-fluorophenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.47 (s, 1H), 9.25 (s, 1H), 8.13 (d, 1H, J=3.5 Hz),8.01-7.98 (m, 2H), 7.84 (s,1H), 7.77-7.74 (m, 1H), 7.50 (s, 2H), 7.34 (app t, 1H, J=9.0 Hz), 3.99 (s, 3H). LCMS: ret. time: 10.80 min.; purity:98%; MS (m/e): 386 (MH⁺). 7.4.414N4-(3-Chloro-4-fluorophenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine(R935427) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidineamine and6-aminoindazoline were reacted to giveN4-(3-chloro-4-fluorophenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.72 (s, 1H), 9.52 (s, 1H), 9.43 (s, 1H), 8.19 (d,1H, J=3.5 Hz), 8.08-8.04 (m, 2H), 7.89-7.83 (m, 2H), 7.58 (d, 1H, J=8.8Hz), 7.35 (t, 1H, J=9.0 Hz), 7.26 (d, 1H, J=8.8 Hz). LCMS: ret. time:10.26 min.; purity: 94%; MS (m/e): 373 (MH⁺). 7.4.415N4-(3-Chloro-4-fluorophenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidinediamine(R935428) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidineamine and5-aminoindazoline were reacted to giveN4-(3-chloro-4-fluorophenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.14 (s, 1H), 9.92 (s, 1H), 8.24 (d, 1H, J=4.9 Hz),7.97-7.89 (m, 3H), 7.69-7.65 (m, 1H), 7.49 (d, 1H, J=8.8 Hz), 7.40 (d,1H, J=10.8 Hz), 7.34 (d, 1H, J=10.8 Hz). LCMS: ret. time: 9.42 min.;purity: 96%; MS (m/e): 373 (MH⁺). 7.4.416N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamineBenzenesulfonic Acid Salt (R935429)N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazine-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine(1.5 g, 3.57 mmol) in MeOH (20 mL) was cooled to 0° C. To the abovecontents, benzenesulfonic acid (0.594 g, 3.75 mmol, 98%) dissolved inCH₃CN (20 ml) was added dropwise for 5 min. The clear solution formedwas stirred (15 min) at the same temperature and allowed to warm to roomtemperature (60 min). The clear solution turned into precipitated form.The reaction mixture was concentrated, dissolved in MeOH (4 mL) andtriturated with EtOAC:n-hexanes. The solid obtained was filtered anddried under high vacuum to provideN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamineBenzenesulfonic Acid Salt. ¹H NMR (DMSO-d₆): δ10.70 (s, 1H), 10.34 (s,1H), 9.99 (s, 1H), 8.21 (d, 1H, J=5.3 Hz), 8.00 (d, 1H, J=1.8 Hz), 7.67(d, 2H, J=8.5 Hz), 7.60-7.57 (m, 2H), 7.34-7.28 (m, 4H), 7.19 (dd, 1H,J=8.8 and 1.8 Hz), 7.10 (d, 1H, J=2.3 Hz), 6.87 (d, 1H, J=8.0 Hz), 1.36(s, 6H). LCMS: ret. time: 8.39 min.; purity: 100%; MS (m/e): 420 (MH⁺).7.4.417N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediaminep-Toluenesulfonic Acid Salt (R935430) In like manner to the preparationofN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediaminebenzenesulfonic acid salt,N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediaminewas reacted with p-toluenesulfonic acid monohydrate to giveN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediaminep-toluenesulfonic acid Salt. ¹H NMR (DMSO-d₆): δ10.70 (s, 1H), 10.22 (s,1H), 9.88 (s, 1H), 8.19 (d, 1H, J=5.3 Hz), 7.99 (d, 1H, J=0.9 Hz), 7.72(s, 1H), 7.64 (d, 1H, J=8.5 Hz), 7.46 (d, 2H, J=8.0 Hz), 7.34 (dd, 1H,J=2.3 and 8.5 Hz), 7.19 (dd, 1H, J=2.3 and 8.5 Hz), 7.12 (s, 1H), 7.10(d, 2H, J=8.0 Hz), 6.87 (d, 1H, J=8.5 Hz), 2.27 (s, 3H), 1.36 (s, 6H).LCMS: ret. time: 8.39 min.; purity: 100%; MS (m/e): 420 (MH⁺). 7.4.418N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935431) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 5-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazine-6-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.79 (s, 1H), 10.48 (s, 1H), 10.36 (s, 1H), 8.25 (d,1H, J=4.9 Hz), 7.91 (s, 1H), 7.87 (s, 1H), 7.63 (d, 1H, J=8.8 Hz), 7.38(dd, 1H, J=1.7 and 8.8 Hz), 7.21 (d, 1H, J=8.8 Hz), 7.19 (s, 1H), 6.89(d, 1H, J=8.8 Hz), 4.58 (t, 2H, J=6.4 Hz), 3.97 (qt, 2H, J=7.0 Hz), 2.89(t, 2H, J=6.4 Hz), 1.36 (s, 6H), 1.06 (t, 3H, J=7.0 Hz). LCMS: ret.time: 9.52 min.; purity: 100%; MS (m/e): 520 (MH⁺). 7.4.419N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine(R935432) In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with diisobutyl lithiumaluminum hydride. Usual workupfollowed by silica gel column chromatographic purification with 2%MeOH:EtOAc providedN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamineas a white solid. LCMS: ret. time: 7.75 min.; purity: 95%; MS (m/e): 478(MH⁺). 7.4.420N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-{1-[2(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine(R935433) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt were reacted to provideN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-{1-[2(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.64 (s, 1H), 9.32 (s, 1H), 9.09 (s, 1H), 8.09 (s,1H), 8.06 (d, 1H, J=3.8 Hz), 7.82 (qt, 1H, J=4.4 Hz), 7.78 (s, 1H), 7.45(app d, 2H, J=8.4 Hz), 7.32-7.27 (m, 1H), 7.21 (s, 1H), 6.89 (d, 1H,J=8.8 Hz), 4.50 (t, 2H, J=7.0 Hz), 2.62 (t, 2H, J=7.0 Hz), 2.50 (d, 3H,J=4.4 Hz), 1.40 (s, 6H). LCMS: ret. time: 7.45 min.; purity: 97%; MS(m/e): 505 (MH⁺). 7.4.421N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamine(R935434) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 6-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.73 (s, 1H), 10.11 (br s, 1H), 8.24 (d, 1H, J=4.7Hz), 7.94 (s, 1H), 7.85 (s, 1H), 7.61 (d, 1H, J=8.5 Hz), 7.29-7.24 (m,3H), 6.86 (d, 1H, J=8.8 Hz), 4.35 (t, 2H, J=6.4 Hz), 3.94 (qt, 2H, J=7.0Hz), 2.83 (t, 2H, J=6.4 Hz), 1.38 (s, 6H), 1.03 (s, 3H). LCMS: ret.time: 10.64 min.; purity: 96%; MS (m/e): 520 (MH⁺). 7.4.422N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-{1-[2-(N-methylaminocarbonyl)ethyl]indazolin-6-yl}-2,4-pyrimidinediamine(R935435) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-6-yl]-5-fluoro-2,4-pyrimidinediamineand Me₂NH.HCl were reacted to provideN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-{1-[2(N-methylaminocarbonyl)ethyl]indazolin-6-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.61 (s, 1H), 9.41 (s, 1H), 9.29 (s, 1H), 8.13 (d,1H, J=3.8 Hz), 7.86 (s, 1H), 7.81 (qt, 1H, J=4.7 Hz), 7.52 (d, 1H, J=8.8Hz), 7.40-7.30 (m, 2H), 7.27-7.25 (app m, 1H), 6.86 (d, 1H, J=8.5 Hz),4.33 (t, 2H, J=6.8 Hz), 2.49 (d, 3H, J=3.8 Hz), 1.39 (s, 6H). LCMS: ret.time: 8.32 min.; purity: 92%; MS (m/e): 505 (MH⁺). 7.4.423N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(methoxycarbonyl)methyl-indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935436) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 5-amino-1-(methoxycarbonyl)methyl-indazoline were reacted to giveN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(methoxycarbonyl)methyl-indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.79 (s, 1H), 10.40 (s, 1H), 10.27 (s, 1H), 8.23 (d,1H, J=5.0 Hz), 7.95 (s, 1H), 7.92 (s, 1H), 7.59 (d, 1H, J=8.8 Hz), 7.38(dd, 1H, J=1.7 and 8.8 Hz), 7.23 (dd, 1H, J=1.7 and 8.8 Hz), 7.19 (s,1H), 6.89 (d, 1H, J=8.8 Hz), 5.36 (s, 2H), 3.66 (s, 3H), 1.36 (s, 6H).LCMS: ret. time: 8.58 min.; purity: 95%; MS (m/e): 492 (MH⁺). 7.4.424N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methylindazolin-5-yl}-2,4-pyrimidinediamine(R935437) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-(methoxycarbonyl)methyl-indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride were reacted to provideN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methylindazolin-5-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.64 (s, 1H), 9.29 (s, 1H), 9.07 (s, 1H), 8.12 (s,1H), 8.06 (d, 1H, J=3.8 Hz), 7.98 (qt, 1H, J=4.7 Hz), 7.80 (s, 1H), 7.46(dd, 1H, J=2.3 and 8.8 Hz), 7.41 (d, 1H, J=8.8 Hz), 7.31 (dd, 1H, J=2.3and 8.8 Hz), 7.22 (app s, 1H), 6.89 (d, 1H, J=8.8 Hz), 4.96 (s, 2H),2.59 (d, 3H, J=4.7 Hz), 1.40 (s, 6H). LCMS: ret. time: 7.44 min.;purity: 100%; MS (m/e): 491 (MH⁺). 7.4.425N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(indazolin-5-yl)-2,4-pyrimidinediamine(R935438) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazolin-5-yl)-4-pyrimidineamine was reacted with6-amine-2,2-dimethyl-4H-benz(1,4)oxazine-3-one to produceN2-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(indazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.97 (s, 1H), 10.55 (s, 1H), 9.30 (s, 1H), 9.04 (s,1H), 8.19 (s, 1H), 8.02 (d, 1H, J=3.8 Hz), 7.94 (s, 1H), 7.59 (dd, 1H,J=2.0 and 8.8 Hz), 7.45 (d, 1H, J=9.1 Hz), 7.17 (d, 1H, J=2.0 Hz), 7.14(s, 1H), 6.72 (d, 1H, J=9.1 Hz), 1.35 (s, 6H). LCMS: ret. time: 7.46min.; purity: 93%; MS (m/e): 420 (MH⁺). 7.4.426N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine(R935439) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(1-methylindazolin-6-yl)-4-pyrimidineamine wasreacted with 6-amine-2,2-dimethyl-4H-benz(1,4)oxazine-3-one to giveN2-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.67 (s, 1H), 10.41 (s, 1H), 10.09 (s, 1H), 8.22 (d,1H, J=4.9 Hz), 8.05 (s, 1H), 7.93 (s, 1H), 7.51 (d, 2H, J=8.8 Hz), 7.05(dd, 1H, J=2.3 and 8.5 Hz), 6.95 (s, 1H), 6.81 (d, 1H, J=8.5 Hz), 4.01(s, 3H), 1.34 (s, 6H). LCMS: ret. time: 8.45 min.; purity: 100%; MS(m/e): 434 (MH⁺). 7.4.427N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(indazolin-6-yl)-2,4-pyrimidinediamine(R935440) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(indazolin-6-yl)-4-pyrimidineamine was reacted with6-amine-2,2-dimethyl-4H-benz(1,4)oxazine-3-one to produceN2-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(indazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.57 (s, 1H), 9.80 (s, 1H), 9.44 (s, 1H), 8.12 (d,1H, J=4.4 Hz), 7.99 (s, 1H), 7.82 (s, 1H), 7.66 (d, 1H, J=8.5 Hz),7.50-7.47 (dd, 1H, J=2.5 and 8.5 Hz), 7.20 (dd, 1H, J=2.5 and 8.5 Hz),7.06 (s, 1H), 6.76 (d, 1H, J=8.5 Hz), 1.34 (s, 6H). LCMS: ret. time:8.26 min.; purity: 95%; MS (m/e): 420 (MH⁺). 7.4.428N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidinediamine(R935441) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine was reactedwith 5-aminoindazoline to produceN4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ12.82 (s, 1H), 9.17 (s, 1H), 9.11 (s, 1H), 8.16 (s,1H), 8.04 (d, 1H, J=3.8 Hz), 7.79 (s, 1H), 7.43 (d, 1H, J=8.8 Hz), 7.35(d, 1H, J=8.8 Hz), 7.28-7.23 (m, 2H), 6.90 (d, 1H, J=8.5 Hz), 3.76 (s,3H), 3.62 (s, 3H). LCMS: ret. time: 7.06 min.; purity: 100%; MS (m/e):381 (MH⁺). 7.4.429N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[1-(2-methoxy-4-methoxycarbonylbenzyl)indazolin-6-yl]-2,4-pyrimidinediamine (R935442) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineaminewas reacted with 6-amino-1-(2-methoxy-4-methoxycarbonylbenzyl)indazolineto provideN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[1-(2-methoxy-4-methoxycarbonylbenzyl)indazolin-6-yl]-2,4-pyrimidinediamine. ¹H NMR (DMSO-d₆): δ10.72 (s, 1H), 10.19 (br s,2H), 8.24 (d, 1H, J=4.7 Hz), 8.00 (d, 1H, J=0.9 Hz), 7.85 (s, 1H), 7.64(d, 1H, J=8.5 Hz), 7.44 (d, 1H, J=1.8 Hz), 7.40 (dd, 1H, J=1.7 and 8.0Hz), 7.26 (dd, 2H, J=1.7 and 8.8 Hz), 7.21 (d, 1H, J=1.8 Hz), 6.81 (d,1H, J=8.5 Hz), 6.76 (d, 1H, J=8.0 Hz), 5.39 (s, 2H), 3.8 (s, 3H), 3.80(s, 3H), 1.34 (s, 6H). LCMS: ret. time: 12.04 min.; purity: 100%; MS(m/e): 598 (MH⁺). 7.4.430N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediaminep-ToluenesulfonicAcid Salt (R935443) In like manner to the preparation ofN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(indazolin-6-yl)-2,4-pyrimidinediaminebenzenesulfonic acid salt,N4-(3,4-dichlorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediaminewas reacted with p-toluenesulfonic acid to giveN4-(3,4-dichlorophenyl)-5-fluoro-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediaminep-toluenesulfonicacid salt. ¹H NMR (DMSO-d₆): δ10.12 (s, 1H), 9.92 (s, 1H), 8.29 (d, 1H,J=4.1 Hz), 8.09 (s, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.74 (d, 1H, J=8.5Hz), 7.66 (d, 1H, J=8.5 Hz), 7.55 (d, 1H, J=8.8 Hz), 7.46 (d, 2H, J=7.9Hz), 7.20 (d, 1H, J=8.5 Hz), 3.82 (s, 3H), 2.27 (s, 3H). LCMS: ret.time: 8.39 min.; purity: 100%; MS (m/e): 420 (MH⁺). LCMS: ret. time:13.48 min.; purity: 97%; MS (m/e): 404 (MH⁺) 7.4.431N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935444) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and2-methyl-6-aminoindazole were reacted to giveN4-(3,4-dichlorophenyl)-5-fluoro-N2-(2-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.59 (s, 1H), 9.33 (s, 1H), 8.20 (d, 1H, J=3.8 Hz),8.16 (s, 1H), 8.10 (t, 1H, J=2.3 Hz), 7.97 (s, 1H), 7.94 (dt, 1H, J=2.3and 8.8 Hz), 7.53 (d, 1H, J=8.5 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.19 (dd,1H, J=1.2 and 8.8 Hz), 4.08 (s, 3H). LCMS: ret. time: 12.08 min.;purity: 100%; MS (m/e): 404 (MH⁺). 7.4.432N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(2-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935445) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 2-methyl-6-aminoindazole were reacted to giveN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-(2-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.77 (s, 1H), 10.69 (s, 1H), 10.65 (s, 1H), 8.35 (d,1H, J=5.3 Hz), 8.31 (s, 1H), 7.86 (s, 1H), 7.64 (d, 1H, J=8.8 Hz), 7.40(s, 1H), 7.19-7.15 (m, 1H), 7.05 (dd, 1H, J=1.5 and 8.8 Hz), 6.90 (d,1H, J=8.5 Hz), 4.12 (s, 3H), 1.40 (s, 6H). LCMS: ret. time: 8.93 min.;purity: 100%; MS (m/e): 434 (MH⁺). 7.4.433N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(2-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935446) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and2-methyl-6-aminoindazole were reacted to giveN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(2-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.34 (s, 1H), 9.22 (s, 1H), 8.14 (s, 1H), 8.11 (d,1H, J=3.8 Hz), 8.03 (s, 1H), 7.84-7.79 (m, 1H), 7.73 (t, 1H, J=2.5 Hz),7.50 (d, 1H, J=9.1 Hz), 7.17 (d, 1H, J=8.9 Hz), 7.15 (d, 1H, J=9.0 Hz),4.06 (s, 3H), 3.88 (s, 3H), 3.88 (s, 3H). LCMS: ret. time: 9.29 min.;purity: 97%; MS (m/e): 399 (MH⁺). 7.4.434N4-(3,4-Dichlorophenyl)-N2-[2-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935447) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and5-amino-2-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(3,4-dichlorophenyl)-N2-[2-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.18 (s, 1H), 9.82 (s, 1H), 8.25 (d, 1H, J=4.7 Hz),8.23 (s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.72 (d, 1H, J=8.8 Hz), 7.57(d, 1H, J=9.4 Hz), 7.52 (d, 1H, J=8.8 Hz), 7.29 (d, 1H, J=9.4 Hz), 4.63(t, 2H, J=6.4 Hz), 4.03 (qt, 2H, J=7.0 Hz), 3.00 (t, 2H, J=6.4 Hz), 1.12(t, 3H, J=7.0 Hz). LCMS: ret. time: 12.53 min.; purity: 95%; MS (m/e):490 (MH⁺). 7.4.435N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935448) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-4-pyrimidineamineand 5-amino-2-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.80 (s, 1H), 10.46 (s, 1H), 10.25 (s, 1H), 8.24 (d,1H, J=5.0 Hz), 8.19 (s, 1H), 7.79 (s, 1H), 7.54 (d, 1H, J=9.1 Hz), 7.23(d, 2H, J=9.1 Hz), 7.19 (s, 1H), 6.88 (d, 1H, J=9.1 Hz), 4.61 (t, 2H,J=6.4 Hz), 4.03 (qt, 2H, J=7.0 Hz), 3.00 (t, 2H, J=6.4 Hz), 1.36 (s,6H), 1.11 (t, 3H, =7.0 Hz). LCMS: ret. time: 8.96 min.; purity: 95%; MS(m/e): 520 (MH⁺). 7.4.4365-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935449) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-fluoro-3-methoxyphenyl)-4-pyrimidineamine and1-methyl-6-aminoindazoline were reacted to give5-fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(1-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.61 (s, 1H), 10.52 (s, 1H), 8.37 (d, 1H, J=5.2 Hz),7.96 (s, 1H), 7.79 (s, 1H), 7.66 (d, 1H, J=8.5 Hz), 7.46 (dd, 1H, J=2.3and 8.0 Hz), 7.27-7.12 (m, 3H), 3.75 (s, 3H), 3.55 (s, 3H). LCMS: ret.time: 10.86 min.; purity: 97%; MS (m/e): 383 (MH⁺). 7.4.4375-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-(2-methylindazolin-6-yl)-2,4-pyrimidinediamine(R935450) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-5-fluoro-N-(4-fluoro-3-methoxyphenyl)-4-pyrimidineamine and2-methyl-6-aminoindazoline were reacted to give5-fluoro-N4-(4-fluoro-3-methoxyphenyl)-5-fluoro-N2-(2-methylindazolin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.18 (s, 1H), 10.08 (s, 1H), 8.28 (s, 1H), 8.26 (d,1H, J=4.8 Hz), 7.84 (s, 1H), 7.61 (d, 1H, J=9.1 Hz), 7.48 (dd, 1H, J=2.3and 8.0 Hz), 7.38-7.34 (m, 1H), 7.18-7.10 (m, 2H), 4.11 (s, 3H), 3.65(s, 3H). LCMS: ret. time: 9.23 min.; purity: 97%; MS (m/e): 383 (MH⁺).7.4.438N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamineBis(p-Toluenesulfonic Acid Salt (R935451) In like manner to thepreparation ofN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4-(indazolin-6-yl)-2,4-pyrimidinediaminebenzenesulfonic acid salt,N4-(3,4-dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediaminewas reacted with 2 eq. of p-toluenesulfonic acid monohydrate. The clearreaction mixture was concentrated, triturated with ether and stirredovernight under N₂. The white precipitate formed was collected byfiltration to giveN4-(3,4-dichlorophenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediaminebisp-toluenesulfonic acid salt. ¹H NMR (DMSO-d₆): δ10.67 (s, 1H), 10.24(s, 1H), 8.31 9d, 1H, J=5.0 Hz), 8.00 (s, 1H), 7.98 (s, 1H), 7.79 (s,1H), 7.69 (d, 1H, J=9.1 Hz), 7.63 (s, 1H), 7.53 (d, 1H, J=8.8 Hz), 7.46(d, 4H, J=8.2 Hz), 7.38 (dd, 1H, J=1.4 and 8.8 Hz), 7.10 (d, 4H, J=8.2Hz), 4.45 (t, 2H, J=6,7 Hz), 3.39 (t, 2H, J=6.7 Hz), 2.27 (s, 6H), 1.96(q, 2H, J=6.7 Hz). LCMS: ret. time: 13.52 min.; purity: 100%; MS (m/e):404 (MH⁺). 7.4.439N4-(3,4-Dichlorophenyl)-5-fluoro-N2-{2-[2-(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine(R935452) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3,4-dichlororophenyl)-N2-[2-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt were reacted to provideN4-(3,4-dichlorophenyl)-5-fluoro-N2-{2-[2-(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.50 (s, 1H), 9.18 (s, 1H), 8.11 (d, 1H, J=3.5 Hz),8.07 (t, 1H, J=2.6 Hz), 8.02 (s, 1H), 7.89 (s, 1H), 7.83 (qt, 1H, J=4.4Hz), 7.80-7.77 (m, 2H), 7.45 (d, 1H, J=8.8 Hz), 7.43 (d, 1H, J=8.8 Hz),7.29 (dd, 1H, J=2.3 and 8.8 hz), 4.51 (t, 2H, J=6.7 Hz), 2.69 (t, 2H,J=6.7 Hz), 2.47 (d, 3H, J=4.4 Hz). LCMS: ret. time: 9.50 min.; purity:93%; MS (m/e): 475 (MH⁺). 7.4.440N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-{2-[2(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine(R935453) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[2-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt were reacted to provideN4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-{2-[2(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.63 (s, 1H), 9.31 (s, 1H), 9.01 (s, 1H), 8.06 (d,1H, J=3.5 Hz), 8.02 (s, 1H), 7.96 (s, 1H), 7.87 (t, 1H, J=4.4 Hz), 7.43(d, 1H, J=8.8 Hz), 7.33-7.25 (m, 3H), 6.88 (d, 1H, J=8.5 Hz), 4.53 (t,2H, J=6.7 Hz), 2.73 (t, 2H, J=6.7 Hz), 2.53 (d, 3H, J=4.4 Hz), 1.41 (s,6H). LCMS: ret. time: 7.19 min.; purity: 100%; MS (m/e): 505 (MH⁺).7.4.441N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine(R935458) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and1-methyl-5-aminoindazole were reacted to giveN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.29 (s, 1H), 10.18 (s, 1H), 8.24 (d, 1H, J=5.0 Hz),7.89 (s, 1H), 7.86 (s, 1H), 7.74 (d, 1H, J=2.3 Hz), 7.60 (d, 1H, J=9.1Hz), 7.54 (dd, 1H, J=2.3 and 8.8 Hz), 7.39 (dd, 1H, J=2.0 and 9.1 Hz),7.09 (d, 1H, J=9.1 Hz), 4.00 (s, 3H), 3.83 (s, 3H). LCMS: ret. time:9.92 min.; purity: 98%; MS (m/e): 401 (MH⁺). 7.4.442N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidinediamine(R935459) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and5-aminoindazoline were reacted to giveN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(indazolin-5-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.59 (s, 1H), 9.40 (s, 1H), 8.10 (d, 1H, J=4.1 Hz),7.97 (s, 1H), 7.87 (s, 1H), 7.79 (d, 1H, J=2.3 Hz), 7.60 (dd, 1H, J=2.3and 8.8 Hz), 7.42 (s, 2H), 7.08 (d, 1H, J=8.8 Hz), 3.84 (s, 3H). LCMS:ret. time: 8.84 min.; purity: 94%; MS (m/e): 388 (MH⁺). 7.4.443N4-(3-Chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine(R935460) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine,2-chloro-N-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and5-amino-1-(2-ethoxycarbonylethyl)indazoline were reacted to giveN4-(3-chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ10.41 (s, 1H), 10.30 (s, 1H), 8.27 (d, 1H, J=5.3 Hz),7.93 (s, 1H), 7.83 (s, 1H), 7.73 (d, 1H, J=2.3 Hz), 7.67 (d, 1H, J=8.8Hz), 7.55 (dd, 1H, J=2.3 and 8.8 Hz), 7.39 (dd, 1H, J=2.3 and 8.8 Hz),7.10 (d, 1H, J=8.8 Hz), 4.59 (t, 2H, J=6.4 Hz), 3.97 (qt, 2H, J=7.0 Hz),3.83 (s, 3H), 2.90 (t, 2H, J=6.4 Hz), 1.06 (t, 3H, J=7.0 Hz). LCMS: ret.time: 11.20 min.; purity: 96%; MS (m/e): 488 (MH⁺). 7.4.444N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine(R935461) In like manner to the preparation ofN2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediaminewas reacted with diisobutyl lithiumaluminum hydride to produceN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.29 (s, 1H), 9.18 (s, 1H), 8.07 (d, 1H, J=3.8 Hz),8.02 (s, 1H), 7.81 (s, 1H), 7.80 (d, 1H, J=2.3 Hz), 7.65 (dd, 1H, J=2.3and 8.8 Hz), 7.48 (app d, 2H, J=8.8 Hz), 7.10 (d, 1H, J=8.8 Hz), 4.58(t, 1H, J=4.7 Hz), 4.37 (t, 2H, J=6.7 Hz), 3.84 (s, 3H), 3.34 (t, 1H,J=6.7 Hz), 1.92 (q, 2H, J=6.7 Hz). LCMS: ret. time: 9.00 min.; purity:98%; MS (m/e): 445 (MH⁺). 7.4.445N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-{1-[2-(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine(R935462) In like manner to the preparation ofN4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine,N4-(3-chloro-4-methoxyphenyl)-N2-[1-(2-ethoxycarbonylethyl)indazolin-5-yl]-5-fluoro-2,4-pyrimidinediamineand methylamine hydrochloride salt were reacted to provideN4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-{1-[2-(N-methylaminocarbonyl)ethyl]indazolin-5-yl}-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ9.31 (s, 1H), 9.20 (s, 1H), 8.08 (d, 1H, J=4.8 Hz),8.02 (s, 1H), 7.84 (qt, 1H, J=4.7 Hz), 7.81 (s, 1H), 7.78 (d, 1H, J=2.6Hz), 7.66 (dd, 1H, J=2.6 and 9.1 Hz), 7.49 (d, 1H, J=9.1 Hz), 7.46 (d,1H, J=9.1 Hz), 7.11 (d, 1H, J=9.1 Hz), 4.51 (t, 2H, J=6.7 Hz), 3.85 (s,3H), 2.63 (t, 2H, J=6.7 Hz), 2.50 (d, 3H, J=4.7 Hz). LCMS: ret. time:8.60 min.; purity: 93%; MS (m/e): 472 (MH⁺).

7.5 The 2,4-Pyrimidinediamine Compounds of the Invention Inhibit FcεRIReceptor-Mediated Degranulation

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit IgE-induced degranulation was demonstrated in a variety ofcellular assays with cultured human mast cells (CHMC) and/or mouse bonemarrow derived cells (BMMC). Inhibition of degranulation was measured atboth low and high cell density by quantifying the release of the granulespecific factors tryptase, histamine and hexosaminidase. Inhibition ofrelease and/or synthesis of lipid mediators was assessed by measuringthe release of leukotriene LTC4 and inhibition of release and/orsynthesis of cytokines was monitored by quantifying TNF-α, IL-6 andIL-13. Tryptase and hexosaminidase were quantified using fluorogenicsubstrates as described in their respective examples. Histamine, TNFα,IL-6, IL-13 and LTC4 were quantified using the following commercialELISA kits: histamine (Immunotech #2015, Beckman Coulter), TNFα(Biosource #KHC3011), IL-6 (Biosource #KMC0061), IL-13 (Biosource#KHC0132) and LTC4 (Cayman Chemical #520211). The protocols of thevarious assays are provided below.

7.5.1 Culturing of Human Mast and Basophil Cells

Human mast and basophil cells were cultured from CD34-negativeprogenitor cells as described below (see also the methods described incopending U.S. application Ser. No. 10/053,355, filed Nov. 8, 2001, thedisclosure of which is incorporated herein by reference).

7.5.1.1 Preparation of STEMPRO-34 Complete Medium

To prepare STEMPRO-34 complete medium (“CM”), 250 mL STEMPRO-34™ serumfree medium (“SFM”; GibcoBRL, Catalog No. 10640) was added to a filterflask. To this was added 13 mL STEMPRO-34 Nutrient Supplement (“NS”;GibcoBRL, Catalog No. 10641) (prepared as described in more detail,below). The NS container was rinsed with approximately 10 mL SFM and therinse added to the filter flask. Following addition of 5 mL L-glutamine(200 mM; Mediatech, Catalog No. MT 25-005-CI and 5 mL 100×penicillin/streptomycin (“pen-strep”; HyClone, Catalog No. SV30010), thevolume was brought to 500 mL with SFM and the solution was filtered.

The most variable aspect of preparing the CM is the method by which theNS is thawed and mixed prior to addition to the SFM. The NS should bethawed in a 37° C. water bath and swirled, not vortexed or shaken, untilit is completely in solution. While swirling, take note whether thereare any lipids that are not yet in solution. If lipids are present andthe NS is not uniform in appearance, return it to the water bath andrepeat the swirling process until it is uniform in appearance. Sometimesthis component goes into solution immediately, sometimes after a coupleof swirling cycles, and sometimes not at all. If, after a couple ofhours, the NS is still not in solution, discard it and thaw a freshunit. NS that appears non-uniform after thaw should not be used.

7.5.1.2 Expansion of CD34+ Cells

A starting population of CD34-positive (CD34+) cells of relatively smallnumber (1-5×10⁶ cells) was expanded to a relatively large number ofCD34-negative progenitor cells (about 2-4×10⁹ cells) using the culturemedia and methods described below. The CD34+ cells (from a single donor)were obtained from Allcells (Berkeley, Calif.). Because there is adegree of variation in the quality and number of CD34+ cells thatAllcells typically provides, the newly delivered cells were transferredto a 15 mL conical tube and brought up to 10 mL in CM prior to use.

On day 0, a cell count was performed on the viable (phase-bright) cellsand the cells were spun at 1200 rpm to pellet. The cells wereresuspended to a density of 275,000 cells/mL with CM containing 200ng/mL recombinant human Stem Cell Factor (“SCF”; Peprotech, Catalog No.300-07) and 20 ng/mL human flt-3 ligand (Peprotech, Catalog No. 300-19)(“CM/SCF/flt-3 medium”). On about day 4 or 5, the density of the culturewas checked by performing a cell count and the culture was diluted to adensity of 275,000 cells/mL with fresh CM/SCF/flt-3 medium. On about day7, the culture was transferred to a sterile tube and a cell count wasperformed. The cells were spun at 1200 rpm and resuspended to a densityof 275,000 cells/mL with fresh CM/SCF/flt-3 medium.

This cycle was repeated, starting from day 0, a total of 3-5 times overthe expansion period.

When the culture is large and being maintained in multiple flasks and isto be resuspended, the contents of all of the flasks are combined into asingle container prior to performing a cell count. This ensures that anaccurate cell count is achieved and provides for a degree of uniformityof treatment for the entire population. Each flask is checked separatelyfor contamination under the microscope prior to combining to preventcontamination of the entire population.

Between days 17-24, the culture can begin to go into decline (i.e.,approximately 5-10% of the total number of cells die) and fail to expandas rapidly as before. The cells are then monitored on a daily basisduring this time, as complete failure of the culture can take place inas little as 24 hours. Once the decline has begun, the cells arecounted, spun down at 850 rpm for 15 minutes, and resuspended at adensity of 350,000 cells/mL in CM/SCF/flt-3 medium to induce one or twomore divisions out of the culture. The cells are monitored daily toavoid failure of the culture.

When greater than 15% cell death is evident in the progenitor cellculture and some debris is present in the culture, the CD34-negativeprogenitor cells are ready to be differentiated.

7.5.1.3 Differentiation of CD34-Negative Progenitor Cells into MucosalMast Cells

A second phase is performed to convert the expanded CD34-negativeprogenitor cells into differentiated mucosal mast cells. These mucosalcultured human mast cells (“CHMC”) are derived from CD34+ cells isolatedfrom umbilical cord blood and treated to form a proliferated populationof CD34-negative progenitor cells, as described above. To produce theCD43-negative progenitor cells, the resuspension cycle for the culturewas the same as that described above, except that the culture was seededat a density of 425,000 cells/mL and 15% additional media was added onabout day four or five without performing a cell count. Also, thecytokine composition of the medium was modified such that it containedSCF (200 ng/mL) and recombinant human IL-6 (200 ng/mL; Peprotech,Catalog No. 200-06 reconstituted to 100 ug/mL in sterile 10 mM aceticacid) (“CM/SCF/IL-6 medium”).

Phases I and II together span approximately 5 weeks. Some death anddebris in the culture is evident during weeks 1-3 and there is a periodduring weeks 2-5 during which a small percentage of the culture is nolonger in suspension, but is instead attached to the surface of theculture vessel. As during Phase I, when the culture is to be resuspendedon day seven of each cycle, the contents of all flasks are combined intoa single container prior to performing a cell count to ensure uniformityof the entire population. Each flask is checked separately forcontamination under the microscope prior to combining to preventcontamination of the entire population.

When the flasks are combined, approximately 75% of the volume istransferred to the communal container, leaving behind about 10 mL or soin the flask. The flask containing the remaining volume was rappedsharply and laterally to dislodge the attached cells. The rapping wasrepeated at a right angle to the first rap to completely dislodge thecells.

The flask was leaned at a 45 degree angle for a couple of minutes beforethe remaining volume was transferred to the counting vessel. The cellswere spun at 950 rpm for 15 min prior to seeding at 35-50 mL per flask(at a density of 425,000 cells/mL).

7.5.1.4 Differentiation of CD34-Negative Progenitor Cells intoConnective Tissue-Type Mast Cells

A proliferated population of CD34-negative progenitor cells is preparedas above and treated to form a tryptase/chymase positive (connectivetissue) phenotype. The methods are performed as described above formucosal mast cells, but with the substitution of IL-4 for IL-6 in theculture medium. The cells obtained are typical of connective tissue mastcells.

7.5.1.5 Differentiation of CD34-Negative Progenitor Cells into

Basophil Cells

A proliferated population of CD34-negative progenitor cells is preparedas described in Section 7.5.1.3, above, and used to form a proliferatedpopulation of basophil cells. The CD34-negative cells are treated asdescribed for mucosal mast cells, but with the substitution of IL-3 (at20-50 ng/mL) for IL-6 in the culture medium.

7.5.2 CHMC Low Cell Density IgE Activation: Tryptase and LTC4 Assays

To duplicate 96-well U-bottom plates (Costar 3799) add 65 ul of compounddilutions or control samples that have been prepared in MT [137 mM NaCl,2.7 mM KCl, 1.8 mM CaCl₂, 1.0 mM MgCl₂, 5.6 mM Glucose, 20 mM Hepes (pH7.4), 0.1% Bovine Serum Albumin, (Sigma A4503)] containing 2% MeOH and1% DMSO. Pellet CHMC cells (980 rpm, 10 min) and resuspend in pre-warmedMT. Add 65 ul of cells to each 96-well plate. Depending on thedegranulation activity for each particular CHMC donor, load 1000-1500cells/well. Mix four times followed by a 1 hr incubation at 37° C.During the 1 hr incubation, prepare 6× anti-IgE solution [rabbitanti-human IgE (1 mg/ml, Bethyl Laboratories A80-109A) diluted 1:167 inMT buffer]. Stimulate cells by adding 25 ul of 6× anti-IgE solution tothe appropriate plates. Add 25 ul MT to un-stimulated control wells. Mixtwice following addition of the anti-IgE. Incubate at 37° C. for 30minutes. During the 30 minute incubation, dilute the 20 mM tryptasesubstrate stock solution [(Z-Ala-Lys-Arg-AMC.2TFA; Enzyme SystemsProducts, #AMC-246)] 1:2000 in tryptase assay buffer [0.1 M Hepes (pH7.5), 10% w/v Glycerol, 10 uM Heparin (Sigma H-4898) 0.01% NaN₃]. Spinplates at 1000 rpm for 10 min to pellet cells. Transfer 25 ul ofsupernatant to a 96-well black bottom plate and add 100 ul of freshlydiluted tryptase substrate solution to each well. Incubate plates atroom temperature for 30 min. Read the optical density of the plates at355 nm/460 nm on a spectrophotometric plate reader.

Leukotriene C4 (LTC4) is also quantified using an ELISA kit onappropriately diluted supernatant samples (determined empirically foreach donor cell population so that the sample measurement falls withinthe standard curve) following the supplier's instructions.

7.5.3 CHMC High Cell Density IgE Activation: Degranulation (Tryptase,Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha, IL-13) Assays

Cultured human mast cells (CHMC) are sensitized for 5 days with IL-4 (20ng/ml), SCF (200 ng/ml), IL-6 (200 ng/ml), and Human IgE (CP 1035K fromCortx Biochem, 100-500 ng/ml depending on generation) in CM medium.After sensitizing, cells are counted, pelleted (1000 rpm, 5-10 minutes),and resuspended at 1-2 ×10⁶ cells/ml in MT buffer. Add 100 ul of cellsuspension to each well and 100 ul of compound dilutions. The finalvehicle concentration is 0.5% DMSO. Incubate at 37° C. (5% CO₂) for 1hour. After 1 hour of compound treatment, stimulate cells with 6×anti-IgE. Mix wells with the cells and allow plates to incubate at 37°C. (5% CO₂) for one hour. After 1 hour incubation, pellet cells (10minutes, 1000 RPM) and collect 200 ul per well of the supernatant, beingcareful not to disturb pellet. Place the supernatant plate on ice.During the 7-hour step (see next) perform tryptase assay on supernatantthat had been diluted 1:500. Resuspend cell pellet in 240 ul of CM mediacontaining 0.5% DMSO and corresponding concentration of compound.Incubate CHMC cells for 7 hours at 37° C. (5% CO₂). After incubation,pellet cells (1000 RPM, 10 minutes) and collect 225 ul per well andplace in −80° C. until ready to perform ELISAS. ELISAS are performed onappropriately diluted samples (determined empirically for each donorcell population so that the sample measurement falls within the standardcurve) following the supplier's instructions.

7.5.4 BMMC High Cell Density IgE Activation: Degranulation(Hexosiminidase, Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha,IL-6) Assays 7.5.4.1 Preparation of WEHI-Conditioned Medium

WEHI-conditioned medium was obtained by growing murine myelomonocyticWEHI-3B cells (American Type Culture Collection, Rockville, Md.) inIscove's Modified Eagles Media (Mediatech, Hernandon, Va.) supplementedwith 10% heat-inactivated fetal bovine serum (FBS; JRH Biosciences,Kansas City, Mo.), 50 μM 2-mercaptoethanol (Sigma, St. Louis, Mo.) and100 IU/mL penicillin-steptomycin (Mediatech) in a humidified 37° C., 5%CO₂/95% air incubator. An initial cell suspension was seeded at 200,000cells/mL and then split 1:4 every 3-4 days over a period of two weeks.Cell-free supernatants were harvested, aliquoted and stored at −80° C.until needed.

7.5.4.2 Preparation of BMMC Medium

BMMC media consists of 20% WEHI-conditioned media, 10% heat-inactivatedFBS (JHR Biosciences), 25 mM HEPES, pH7.4 (Sigma), 2 mM L-glutamine(Mediatech), 0.1 mM non-essential amino acids (Mediatech), 1 mM sodiumpyruvate (Mediatech), 50 μM 2-mercaptoethanol (Sigma) and 100 IU/mLpenicillin-streptomycin (Mediatech) in RPMI 1640 media (Mediatech). Toprepare the BMMC Media, all components are added to a sterile IL filterunit and filtered through a 0.2 μm filter prior to use.

7.5.4.3 Protocol

Bone marrow derived mast cells (BMMC) are sensitized overnight withmurine SCF (20 ng/ml) and monoclonal anti-DNP (10 ng/ml, Clone SPE-7,Sigma # D-8406) in BMMC media at a cell density of 666×10³ cells/ml.After sensitizing, cells are counted, pelleted (1000 rpm, 5-10 minutes),and resuspended at 1-3×10⁶ cells/ml in MT buffer. Add 100 ul of cellsuspension to each well and 100 ul of compound dilutions. The finalvehicle concentration is 0.5% DMSO. Incubate at 37° C. (5% CO₂) for 1hour. After 1 hour of compound treatment, stimulate cells with 6×stimulus (60 ng/ml DNP-BSA). Mix wells with the cells and allow platesto incubate at 37° C. (5% CO₂) for one hour. After 1 hour incubation,pellet cells (10 minutes, 1000 RPM) and collect 200 ul per well of thesupernatant, being careful not to disturb pellet, and transfer to aclean tube or 96-well plate. Place the supernatant plate on ice. Duringthe 4-5 hour step (see next) perform the hexosiminidase assay. Resuspendcell pellet in 240 ul WEI-conditioned media containing 0.5% DMSO andcorresponding concentration of compound. Incubate BMMC cells for 4-5hours at 37° C. (5% CO₂). After incubation, pellet cells (1000 RPM, 10minutes) and collect 225 ul per well and place in −80° C. until ready toperform ELISAS. ELISAS are performed on appropriately diluted samples(determined empirically for each donor cell population so that thesample measurement falls within the standard curve) following thesupplier's instructions.

Hexosaminidase assay: In a solid black 96-well assay plate, add 50 uLhexosaminidase substrate(4-methylumbelliferyl-N-acetyl-β-D-glucosaminide; 2 mM) to each well.Add 50 uL of BMMC cell supernatant (see above) to the hexoseaminidasesubstrate, place at 37° C. for 30 minutes and read the plate at 5, 10,15, and 30 minutes on a spectrophotometer.

7.5.5 Basophil IgE or Dustmite Activation: Histamine Release Assay

The basophil activation assay was carried out using whole humanperipheral blood from donors allergic to dust mites with the majority ofthe red blood cells removed by dextran sedimentation. Human peripheralblood was mixed 1:1 with 3% dextran T500 and RBCs were allowed to settlefor 20-25min. The upper fraction was diluted with 3 volumes of D-PBS andcells were spun down for 10 min at 1500 rpm, RT. Supernatant wasaspirated and cells were washed in an equal volume MT-buffer. Finally,cells were resuspended in MT-buffer containing 0.5% DMSO in the originalblood volume. 80 uL cells were mixed with 20 uL compound in the presenceof 0.5% DMSO, in triplicate, in a V-bottom 96-well tissue culture plate.A dose range of 8 compound concentrations was tested resulting in a10-point dose response curve including maximum (stimulated) and minimum(unstimulated) response. Cells were incubated with compound for 1 hourat 37° C., 5% CO₂ after which 20 uL of 6× stimulus [1 ug/mL anti-IgE(Bethyl Laboratories) 667 au/mL house dustmite (Antigen Laboratories)]was added. The cells were stimulated for 30 minutes at 37° C., 5% CO₂.The plate was spun for 10 min at 1500 rpm at room temperature and 80 uLthe supernatant was harvested for histamine content analysis using thehistamine ELISA kit supplied by Immunotech. The ELISA was performedaccording to supplier's instructions.

7.5.6 Results

The results of low density CHMC assays (Section 7.5.2), the high densityBMMC assays (Section 7.5.4) and the basophil assays (Section 7.5.5) areprovided in TABLE 1. The results of the high density CHMC assays(Section 7.5.3) are provided in TABLE 2. In TABLES 1 and 2, all reportedvalues are IC₅₀s (in μM). A value of “9999” indicates an IC₅₀>10 μM,with no measurable activity at a 10 μM concentration. Most compoundstested had IC₅₀s of less than 10 μM, with many exhibiting IC₅₀s in thesub-micromolar range.

7.6 The 2,4-Pyrimidinediamine Compounds Inhibit FcγRI Receptor-MediatedDegranulation

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit FcγRI-mediated degranulation was demonstrated with CompoundsR921218, R921302, R921303, R940347, R920410, R927050, R940350, R935372,R920323, R926971 and R940352 in assays similar to those described inSection 7.5, with the exception that the cells were not primed with IgEand were activated with rabbit anti-human IgG Fab fragment (BethylLaboratories, Catalog No. A80-105).

All of the compounds tested exhibited IC₅₀s in the sub micromolar range.

TABLE 1 Low Density CHMC CHMC CHMC CHMC CHMC Basophils BasophilsBasophils Test anti-IgE Ionomycin anti-IgE anti-IgE Ionomycin anti-IgEIonomycin Dust mite Compound Tryptase Tryptase LTC4 Hexos. Hexos.Histamine Histamine Histamine R008951 R008952 R008953 R008955 R008956R008958 R067934 R067963 R070153 R070790 1.665 9999 R070791 R081166R088814 R088815 R091880 R092788 R908696 3.553 R908697 9999 9999 R9092360.996 9999 R909237 9999 9999 R909238 0.174 9999 R909239 0.264 9999R909240 0.262 9999 R909241 0.181 9999 R909242 0.567 9999 R9092430.263 >10 R909245 0.255 6.242 R909246 0.169 9999 R909247 2.393 9999R909248 3.582 9999 R909249 9999 9999 R909250 8.025 9999 R909251 0.1389999 R909252 0.248 9999 R909253 7.955 9999 R909254 0.136 9999 R9206649999 9999 R920665 1.1 9999 R920666 2.53 9999 R920668 3.2 9999 R9206690.42 9999 R920670 2.18 9999 R920671 9999 9999 R920672 9999 9999 R9208189999 9999 R920819 10 9999 R920820 9999 9999 R920846 9999 9999 R9208601.009 9999 R920861 0.598 >10 R920893 1.239 9999 R920894 0.888 5.566R920910 0.751 7.922 R920917 1.579 9.729 R921218 0.499 9999 0.55 0.6 99990.24 9999 0.302 R921219 0.059 9999 0.025 9999 0.020 R925734 9.2 >10R925747 1.021 3.1 R925755 0.898 9999 R925757 2.8 9999 R925758 1.175 9999R925760 4.85 9999 R925765 6.8 9999 R925766 8.9 9999 R925767 10 R9257689999 R925769 9999 R925770 9999 R925771 0.5 2.8 0.22 R925772 9999 9999R925773 0.673 9999 R925774 0.435 9999 R925775 0.225 9999 0.2 R925776 2.19999 R925778 0.225 9999 0.18 R925779 0.265 9999 0.19 R925783 2.9 9999R925784 3.2 9999 R925785 2.5 9999 R925786 1.85 9999 R925787 9 9999R925788 2.4 9999 R925790 9999 9999 R925791 9999 9999 R925792 6.25 9999R925794 9999 9999 R925795 9999 9999 R925796 2 9999 R925797 0.85 99990.28 R925798 9999 9999 R925799 9999 9999 R925800 9999 9999 R925801 99999999 R925802 9999 9999 R925803 9999 9999 R925804 9999 9999 R925805 99999999 R925806 9999 9999 R925807 9999 9999 R925808 9999 9999 R925810 99999999 R925811 3.3 9999 R925812 5.8 9999 R925813 9999 9999 R925814 99999999 R925815 9999 9999 R925816 6 9999 R925819 9999 9999 R925820 99999999 R925821 9999 9999 R925822 9999 9999 R925823 9999 9999 R925824 99999999 R925837 9999 9999 R925838 9999 9999 R925839 9999 9999 R925840 99999999 R925841 9999 9999 R925842 7.3 9999 R925843 9999 9999 R925844 5.19999 R925845 2.3 9999 R925846 9999 9999 R925849 8.2 9999 R925851 0.9259999 R925852 3 9999 R925853 9999 9999 R925854 9999 9999 R925855 4.2 9999R925856 9.85 9999 R925857 5.95 9999 R925858 8.05 7.3 R925859 9999 9999R925860 9999 9999 R925861 9999 9999 R925862 0.7 9999 R925863 0.274 9999R925864 9999 9999 R925865 9999 9999 R926016 9999 9999 R926017 1.43 99990.53 9999 R926018 9999 10 R926037 9999 9999 R926038 9999 9999 R9260399999 9999 R926058 9999 9999 R926064 6.2 R926065 3.5 R926068 >10 R9260699.1 R926072 >10 R926086 2.5 9999 R926108 0.76 0.787 6.4 0.95 9999R926109 0.538 5.5 0.73 0.55 >10 0.15 9999 R926110 1.071 9999 1.421.2 >10 0.3 9999 R926113 0.413 0.49 0.413 9999 0.27 9999 R926114 3.4278.1 1.7 10 R926145 4.764 >10 R926146 1.59 0.761 6.7 R926147 1.899 >10R926206 >10 >10 R926209 >10 9999 R926210 0.926 9999 0.8 700 99990.37 >10 R926211 1.299 9.8 2.7 9999 1.55 >10 R926212 0.654 9999 0.450.5 >10 R926213 1.639 5.5 1.75 >10 R926218 >10 R926219 1.102 6.7R926220 >10 R926221 8.5 R926222 >10 R926223 >10 R926224 >10 R926225 >10R926228 >10 R926229 >10 R926230 >10 R926234 >10 R926237 1.207 6.2R926240 0.381 1.7 0.145 R926241 7 9999 R926242 4.2 9999 R926243 3.1 9999R926245 3.1 9.4 R926248 0.9 9999 0.76 R926249 0.5 9999 0.25 R926252 2.8R926253 0.8 0.675 R926254 1.3 4 R926255 1.4 4.5 R926256 0.275 5.1 0.23R926257 1.5 7.5 R926258 0.9 9999 0.59 R926259 2.5 6.2 R926319 9999 9999R926320 9999 9999 R926321 9999 9999 R926325 9999 9999 R926331 9999 9999R926339 0.66 9999 R926340 3.23 9999 R926341 0.875 9999 R926342 10 9999R926376 9999 R926386 9999 9999 R926387 0.65 9999 0.7 R926394 9999 9999R926395 0.875 6.4 0.29 R926396 0.7 2.6 0.16 R926397 9999 9999 R9263989999 9999 R926399 9999 9999 R926400 9999 9999 R926401 9999 9999 R9264029999 9999 R926403 9999 9999 R926404 9999 9999 R926405 3.4 9999 R9264069999 9999 R926408 9.6 9999 R926409 3.15 9999 R926411 0.69 2.5 R9264120.62 9999 R926461 0.725 9999 R926467 1.175 8.8 R926469 9999 R926474 2.59999 R926475 2.15 >10 R926476 0.6 7.7 R926477 0.27 9999 R926478 9999R926479 9999 R926480 1.9 9999 R926481 1.445 9999 R926482 1.037 >10R926483 9999 R926484 1.523 9999 R926485 4.012 9999 R926486 0.647 7.403R926487 0.554 8.867 1.25 R926488 0.331 >10 0.752 R926489 1.414 >10R926490 1.571 9999 R926491 1.158 >10 R926492 0.645 9999 R926493 0.259.181 0.078 R926494 0.313 9999 0.078 R926495 0.121 >10 0.078 0.04 99990.038 R926496 0.571 >10 R926497 0.138 9999 0.27 9999 0.205 R9264980.209 >10 R926499 0.29 >10 R926500 0.418 >10 R926501 0.298 >10 0.6099999 0.645 R926502 0.483 >10 0.405 9999 0.491 R926503 0.452 >10 R9265040.569 >10 R926505 0.145 9999 R926506 0.343 9999 R926508 0.127 9999 0.0659999 0.054 R926509 1.16 9999 R926510 0.44 >10 R926511 0.786 >10 R9265149999 9999 R926516 1 9999 R926526 9999 9999 R926527 9999 9999 R9265288.75 9999 R926535 9999 9999 R926536 9999 9999 R926555 9999 9999 R9265597.7 9999 R926560 9999 9999 R926562 9999 9999 R926563 9999 9999 R9265643.75 9999 R926565 0.625 3.3 R926566 2.73 9999 R926567 9.3 9999 R9265690.61 3.07 R926571 9999 9999 R926572 1.8 6.08 R926574 1.96 2.63 R9265769999 9999 R926579 9999 9999 R926580 10 9999 R926582 1.3 9999 R9265839999 9999 R926584 9999 9999 R926585 9999 9999 R926586 2.75 9999 R9265879999 9999 R926588 7.85 9999 R926589 0.325 10 R926591 2.62 9999 R9265930.68 8.3 0.495 R926594 9999 9999 R926595 4.85 9999 R926604 2.85 9999R926605 2.45 9999 R926614 0.228 9999 R926615 0.445 9999 R926616 0.6253.25 R926617 9.45 9999 R926620 8.35 9999 R926623 9999 9999 R926662 99999999 R926663 9999 9999 R926675 0.63 9999 R926676 0.76 9999 R926680 1.719999 R926681 0.775 9999 R926682 8.41 9999 R926683 10 9999 R9266882.25 >10 R926690 0.146 >10 R926696 0.309 >10 R926698 9999 R926699 0.769999 R926700 0.157 >10 R926701 2.2 9999 R926702 0.886 9999 R926703 0.5259999 R926704 0.564 9999 R926705 0.263 9999 0.533 R926706 0.07 2.4060.078 R926707 0.214 9999 R926708 0.472 9999 R926709 0.858 9999 R9267101.763 9999 R926711 1.245 9999 R926712 1.084 9999 R926713 0.446 8.741R926714 0.428 >10 R926715 0.588 >10 R926716 1.06 9999 R926717 7.874 9999R926718 1.826 9999 R926719 0.1335 4.024 R926720 1.555 9999 R926721 4.4419999 R926722 5.96 9999 R926723 2.591 9999 R926724 2.059 9999 R9267250.431 9999 R926726 9999 9999 R926727 0.387 9999 R926728 0.482 >10R926730 0.251 9999 R926731 9999 9999 R926732 0.444 9999 R926733 1.4969999 R926734 4.493 9999 R926735 3.712 9999 R926736 0.288 9999 R9267370.059 9999 R926738 0.342 9999 R926739 0.508 9999 R926740 4.422 9999R926741 2.908 9999 R926742 0.127 0.043 9999 0.055 R926743 9999 R9267449999 R926745 0.083 9999 R926746 0.989 9999 R926747 0.213 >10 R9267480.345 >10 R926749 0.472 9999 R926750 0.361 >10 R926751 0.598 9999R926764 0.252 5.64 R926765 0.324 4.39 R926766 0.756 9999 R9267670.387 >10 R926768 0.443 >10 R926769 1.067 9999 R926770 0.583 9999R926771 2.049 9999 R926772 0.337 7.501 R926773 0.548 7.849 R926774 1.9347.935 R926775 3.47 >10 R926776 0.81 9999 R926777 0.378 9999 R9267780.414 9999 R926779 9999 9999 R926780 0.152 >10 R926781 0.573 9999R926782 0.173 >10 R926783 0.304 >10 R926784 0.252 9999 R926785 0.222 >10R926786 0.504 9999 R926787 5.422 9999 R926788 0.336 6.341 R926789 2.3159999 R926790 0.462 7.412 R926791 0.233 >10 R926792 3.197 9999 R9267933.073 9999 R926795 2.041 >10 R926796 0.914 9999 R926797 2.235 9999R926798 2.347 5.87 R926799 9999 9999 R926800 4.581 9999 R926801 10 9999R926802 1.251 >10 R926803 1.541 >10 R926804 1.578 7.109 R926805 0.7649999 R926806 0.374 9999 R926807 0.291 9999 R926808 0.368 9999 R9268090.78 3.052 R926810 1.221 9999 R926811 3.662 9999 R926812 0.185 >10R926813 0.152 9999 R926814 1.101 9999 R926815 1.181 9999 R926816 0.0849999 R935000 9999 9999 R935001 9999 9999 R935002 9999 9999 R935003 99999999 R935004 9999 9999 R935005 9999 9999 R935006 10 9.8 R935016 99999999 R935019 8.8 9999 R935020 9999 9999 R935021 9999 9999 R935023 99999999 R935025 1.04 9999 R935029 2.83 9999 R935075 0.93 9999 R935076 4.159999 R935077 9999 9999 R935114 1.725 9999 R935117 9999 R935134 0.9091.799 R935135 10 9999 R935136 0.952 2.129 R935137 10 9999 R935138 0.0960.552 R935139 0.846 9999 R935140 0.275 0.959 R935141 0.727 >10 R9351420.873 >10 R935143 0.573 >10 R935144 0.63 9999 R935145 0.548 >10 R9351463.802 9999 R935147 1.404 9999 R935148 2.218 9.423 R935149 0.708 >10R935150 1.926 9.738 R935151 0.479 >10 R935152 0.505 9.316 R9351530.238 >10 R935154 0.127 >10 R935155 0.401 9999 R935156 0.149 >10 R9351570.256 4.656 R935158 0.551 >10 R935159 0.232 4.135 R935160 0.202 >10R935161 0.277 9999 R935162 0.269 >10 R935163 9999 9999 R935164 0.2049999 R935165 4.988 9999 R935166 0.568 9999 R935167 2.132 >10 R9351680.488 9.484 R935169 0.999 8.007 R935170 0.673 9999 R935171 0.536 9999R935172 1.385 6.808 R935173 0.454 >10 R935174 1.384 9999 R935175 0.8859999 R935176 1.169 9999 R935177 0.889 >10 R935178 0.515 9999 R9351790.557 9999 R935180 1.22 9999 R935181 1.76 9999 R935182 0.124 2.469R935183 0.729 9999 R935184 0.605 9999 R935185 0.351 6.642 R935186 0.2119999 R935187 9.059 >10 R935188 0.239 9999 R935189 0.619 9999 R9351900.156 9999 R935191 0.151 9999 R935192 0.337 9999 R935193 0.136 9999R935194 0.11 9999 R935196 0.117 9999 R935197 0.174 >10 R935198 0.126 >10R935199 0.45 >10 R935202 0.181 9.765 R935203 0.562 >10 R935204 0.5549999 R935205 2.959 9999 R935206 4.711 9999 R935207 9999 9999 R9352081.274 9999 R935209 0.526 1.035 R935211 1.238 9999 R935212 1.427 9999R935213 0.619 10 R935214 0.453 5.499 R935218 4.712 9999 R935219 5.4099999 R935220 3.789 9999 R940089 9999 9999 R940090 9999 9999 R940095 99999999 R940100 9999 9999 R940215 0.845 9999 R940216 0.2675 7.3 R9402179999 9999 R940222 9999 9999 R940233 0.132 >10 R940235 0.8 >10 R940250R940251 R940253 1.006 >10 R940254 0.986 9999 R940255 1.033 9999 R9402561.104 9999 R940257 0.667 9999 R940258 0.473 5.72 R940260 1.126 9999R940261 9999 9999 R940262 9999 9999 R940263 9999 9999 R940264 10 9999R940265 0.239 >10 R940266 9999 9999 R940267 3.151 9999 R940269 1.6549999 R940270 2.144 8.739 R940271 0.401 6.821 R940275 0.862 9999 R9402760.211 9999 R940277 0.141 9999 R940280 6.999 9999 R940281 0.525 5.529R940282 0.401 3.015 R940283 0.553 4.982 R940284 0.465 3.744 R9402853.499 9999 R940286 0.337 7.082 R940287 0.288 7.684 R940288 0.208 9999R940289 0.272 9999 R940290 0.116 9999 R940291 0.396 9999 R940292 0.6839999 R940293 9999 9999 R940294 1.366 9999 R940295 0.126 8.812 R9402960.41 >10 R940297 3.465 10 R945025 9999 9999 R945032 0.37 9999 R9450339999 9999 R945034 1.85 9999 R945035 9999 9999 R945036 9999 9999 R9450379999 9999 R945038 9999 9999 R945040 9999 9999 R945041 9999 9999 R9450429999 9999 R945043 9999 9999 R945045 9999 9999 R945046 0.82 >10 R9450470.845 9999 R945048 0.76 9999 R945051 0.95 >10 R945052 0.425 2.48 R9450530.1185 1.48 R945056 10 9999 R945057 10 9999 R945060 0.9375 >10 R94506110 9999 R945062 0.625 >10 R945063 1.55 >10 R945064 0.53 >10 R9450651.425 >10 R945066 5.2 nd R945067 9999 nd R945068 9999 nd R9450700.45 >10 R945071 0.205 >10 R945096 1.75 >10 R945097 10 9999 R9451091.025 >10 R945110 0.602 9999 R945117 4.077 9999 R945118 0.668 9999R945124 0.69 7.852 R945125 0.896 >10 R945126 9999 9999 R945127 0.7048.955 R945128 0.685 8.8 R945129 1.003 >10 R945130 1.874 9999 R9451310.77 9999 R945132 0.571 8.77 R945133 1.064 >10 R945134 9999 9999 R9451350.986 8.245 R945137 1.649 >10 R945138 1.058 6.733 R945139 1.016 >10R945140 0.573 >10 R945142 1.049 >10 R945144 0.244 9999 R945145 9999 >10R945146 3.756 9999 R945147 3.546 9999 R945148 0.307 9999 R9451490.391 >10 R945150 0.467 >10 R945151 4.07 9999 R945152 6.94 9999 R9451530.688 6.561 R945155 1.878 >10 R945156 0.787 9999 R945157 1.477 9999R945162 9999 9999 R945163 0.922 4.251 R945164 10 9999 R945165 9999 9999R945166 9999 9999 R945167 0.761 9999 R945168 10 9999 R945169 10 9999R945170 0.661 >10 R945171 1.327 9999 R945172 1.179 9999 R945173 1.4199999 R945175 1.648 9999 R950082 9999 9999 R950083 9999 9999 R950090 99999999 R921302 0.37 9999 0.19 9999 0.282 R950092 9999 9999 R950093 0.645.55 R950100 0.71 >10 R950107 0.46 >10 R950108 2.075 >10 R950109 7.95R950120 3 9999 R950121 4.25 >10 R950122 3.025 9999 R950123 3.25 8.45R950125 1.375 6.3 R950129 0.665 >10 R950130 4.9 R950131 9999 R950132 9R950133 2.2 >10 R950134 1.875 9999 R950135 0.85 >10 R950137 2.23 9999R950138 9.5 R950139 1.375 9999 R950140 2.825 9999 R950141 0.31 >10R950142 10 R950143 8.23 R950144 10 R950145 9999 R950146 9999 R9501479999 R950148 2.275 9999 R950149 10 9999 R950150 9999 9999 R950151 9999R950152 10 R950153 9999 R950154 2.075 9999 R950155 9999 R950156 9999R950157 9999 R950158 9.98 R950159 0.61 9999 R950160 1 9999 R9501620.434 >10 R950163 0.874 9999 R950164 1.893 9999 R950165 1.288 9999R950166 1.889 9999 R950167 9999 9999 R950168 6.496 8.653 R950169 1.2739.518 R950170 9999 9999 R950171 0.585 >10 R950172 0.983 9999 R9501732.368 >10 R950174 4.618 9999 R950175 1.688 9999 R950176 1.342 9999R950177 2.361 8.434 R950178 0.688 >10 R950179 0.955 >10 R950180 0.2789999 R950181 0.254 9999 R950182 0.627 9999 R950183 4.797 9999 R9501842.222 9999 R950185 1.03 8.81 R950186 0.558 >10 R950187 0.724 >10 R9501882.327 9999 R950189 10 9999 R950190 1.573 9999 R950191 0.178 9999 R9501920.244 9999 R950193 0.61 9999 R950194 2.04 9999 R950195 0.473 9999R950196 2.2 9999 R950197 0.531 9999 R950198 0.406 >10 R950199 0.408 9999R950200 0.245 9999 R950201 0.261 9999 R950202 3.218 9999 R950203 9.0359999 R950204 6.285 9999 R950205 8.997 9999 R950206 3.66 >10 R9502070.164 9999 R950208 0.267 9999 R950209 0.748 9999 R950210 10 9999 R95021110 9999 R950212 0.253 9999 R950213 9999 9999 R950214 10 9999 R9502150.409 9999 R950216 0.327 9999 R950217 0.34 9999 R950218 0.292 9999R950219 0.439 9999 R950220 0.489 9999 R950221 0.636 9999 R950222 0.8659999 R950223 0.763 9999 R950224 0.687 9999 R950225 5.283 9999 R9502261.374 9999 R950227 1.029 9999 R950229 0.98 9999 R950230 7.91 9999R950231 1.968 9999 R950232 10 9999 R950233 0.98 9999 R950234 10 9999R950235 4.095 9999 R950236 0.955 9999 R950237 9999 9999 R950238 10 9999R950239 2.063 9999 R950240 1.766 9999 R950241 3.275 9999 R950251 99999999 R950253 0.697 9999 R950254 0.496 9999 R950255 10 9999 R908698 1.679999 R908699 0.217 9999 R908700 1.273 9999 R908701 0.099 7.643 R9087020.104 7.395 R908703 0.63 9999 R908704 0.511 9999 R908705 0.801 9999R908706 0.445 9999 R908707 1.834 9999 R908709 2.414 R908710 1.838 99R908711 1.761 R908712 0.075 99 R908734 1.379 R909255 0.244 9999 R9092590.43 9999 R909260 1.041 9999 R909261 0.93 9999 R909263 0.289 9999R909264 R909265 99 R909266 99 R909267 0.589 9999 R909268 0.071 9999R909290 0.226 R909292 1.172 R909308 0.671 9999 R909309 0.083 9999R920394 R920395 0.092 9999 R920396 R920397 R920398 R920399 R920404R920405 R920406 R920407 R920408 R920410 0.125 9999 R920411 0.564 9999R925745 1.766 9999 R926238 9999 R926752 0.338 9999 R926753 0.108 9999R926754 0.388 9999 R926755 1.693 9999 R926756 1.365 9999 R926757 0.1589999 R926759 0.688 9999 R926760 2.893 9999 R926761 0.245 9999 R9267620.386 9999 R926763 0.195 9999 R926794 1.382 9999 R926826 0.613 9999R926827 1.098 9999 R926828 0.306 9999 R926829 0.688 9999 R926830 0.56910 R926831 0.133 10 R926832 0.365 9999 R926833 1.129 9999 R926834 0.1459999 R926835 0.296 9999 R926836 10 9999 R926837 2.994 9999 R926838 0.5839999 R926839 0.161 9999 R926840 1.1 9999 R926841 0.551 9999 R9268427.733 9999 R926843 7.371 9999 R926844 1.1 9999 R926845 2.558 7.812R926846 0.86 6.264 R926847 1.479 6.264 R926848 0.254 10 R926851 0.446R926855 9999 9999 R926856 0.734 9999 R926857 1.209 9999 R926859 R9268601.949 99 R926862 0.774 9999 R926863 R926866 R926870 3.294 R926871 2.146R926874 0.638 9999 R926879 0.397 9999 R926880 R926881 R926883 R926885R926886 R926887 1.747 R926890 0.361 9999 R926891 0.152 9999 R9268920.685 9999 R926893 10 9999 R926894 9999 9999 R926895 0.339 9999 R9268961.622 9999 R926897 1.727 9999 R926898 1.1 9999 R926899 1.1 9999 R9269009999 9999 R926902 1.37 4.586 R926903 0.243 9999 R926904 0.538 R926905 99R926906 0.794 R926907 0.764 R926908 0.585 R926909 0.379 R926913 0.5489999 R926914 1.86 9999 R926915 1.713 9999 R926916 1.958 9999 R9269171.169 9999 R926918 2.521 9999 R926919 1.413 9999 R926922 0.305 9999R926923 0.346 9999 R926925 0.307 99 R926926 0.401 9999 R926927 0.3489999 R926928 0.575 9999 R926929 1.916 9999 R926930 99 9999 R926931R926932 0.31 9999 R926933 R926934 R926935 4.44 R926936 R926937 R926938R926939 3.615 R926940 7.754 R926941 4.195 R926942 4.81 R926943 R9269440.225 99 R926945 0.457 9999 R926946 R926947 0.354 9999 R926948 0.2469999 R926949 0.089 9999 R926950 99 9999 R926951 0.183 9999 R926953 0.0499999 R926954 0.284 9999 R926955 0.36 9999 R926956 0.211 9999 R9270161.408 R927017 2.449 R927018 1.446 R927019 1.179 R927020 1.316 9999R927023 0.918 9999 R935221 9999 9999 R935222 0.52 9999 R935223 0.4699999 R935224 4.578 9999 R935225 6.495 9999 R935237 0.24 9999 R9352381.854 9999 R935239 0.609 9999 R935240 0.606 9999 R935242 2.855 9999R935248 1.1 9999 R935249 1.1 9999 R935250 1.1 9999 R935251 R935252R935253 R935255 0.374 9999 R935256 0.324 9999 R935258 1.191 9999 R9352591.777 9999 R935261 0.391 9999 R935262 0.516 9999 R935263 0.106 10R935264 0.135 9999 R935266 2.97 R935267 2.463 R935268 1.059 R9352691.715 R935271 R935276 2.33 R935277 22.883 8.9 R935278 4.753 9999 R9352790.889 9999 R935280 99 R935281 1.399 9999 R935286 1.158 9999 R9352870.403 9999 R935288 1.58 9999 R935289 1.688 9999 R935290 0.34 9999R935291 1.364 9999 R935292 0.483 9999 R935293 0.141 9999 R935294 0.3889999 R935295 1.943 9999 R935296 99 9999 R935297 7.328 9999 R935298 0.25299 R935299 0.21 9999 R935300 0.243 9999 R935301 4.05 99 R935302 0.1899999 R935303 0.244 99 R935304 0.188 9999 R935305 0.495 9999 R9353060.345 99 R935307 0.139 99 R935308 0.275 9999 R935309 R935310 R9353202.769 R935321 2.986 R935322 3.416 R935323 9999 R935324 9999 R9353360.341 9999 R935337 9999 R935338 0.411 9999 R935339 9999 R935340 3.606R935351 9999 9999 R935352 R935353 9999 9999 R935354 99 9999 R935355 99999999 R935356 99 R935357 99 9999 R935358 9999 9999 R935359 1.027 9999R935360 0.903 9999 R935361 1.438 9999 R935362 0.409 9999 R935363 0.4059999 R935364 0.563 9999 R935365 0.373 9999 R935366 0.216 9999 R9353670.053 9999 R940079 9999 R940110 9999 9999 R940299 2.497 9999 R940300 109999 R940301 1.975 9999 R940304 9999 9999 R940306 1.1 9999 R940307 0.2919999 R940308 0.612 4.168 R940309 1.132 9999 R940311 1.95 R940312 2.557R940314 4.197 R940316 1.858 R940317 0.913 9999 R940318 3.792 R9403199999 R940321 9999 R940323 0.048 9999 R940337 1.098 R940338 0.073 9999R921303 0.033 99 R940345 1.712 R940346 0.142 99 R940347 0.063 99 R9403482.189 R940349 0.044 7.4 R940350 0.092 4 R940351 0.12 2.7 R940352 0.1019999 R940353 0.091 9999 R940354 0.115 99 R945236 0.562 9999 R9452370.461 9999 R945242 0.247 9999 R945263 1.642 R921304 0.085 9999 R945299R950244 9999 R950245 9999 R950246 9999 R950247 9999 R950261 0.611 9999R950262 0.285 9999 R950263 0.284 3.299 R950264 0.198 9999 R950265 0.3129999 R950266 0.645 9999 R950267 0.18 9999 R950290 9999 9999 R950291 99999999 R950293 3.689 8.155 R950294 2.005 8.005 R950295 2.041 8.795 R9502960.495 9999 R950344 99 R950345 1.962 99 R950346 0.345 9999 R950347 0.548R950348 0.066 R950349 0.078 9999 R950356 R950368 0.038 9999 R950371R950372 1.348 9999 R950373 R950374 0.599 9999 R950376 2.539 R950377 99R950378 R950379 0.545 9999 R950380 3 9999 R950381 0.11 99 R950382R950383 0.114 9999 R950385 R950386 0.973 R950388 2.518 R950389 0.6129999 R950391 999 9999 R950392 0.956 9999 R950393 0.404 9999 R945028R935241 R940298 R940302 R940303 R940305 R935260 9999 R909258 R9403139999 R940315 9999 R935275 9999 R940320 9999 R940322 9999 9999 R9269109999 9999 R926911 9999 9999 R926912 9999 9999 R926853 9999 9999 R9268529999 9999 R926854 9999 9999 R926920 9999 9999 R926921 99 9999 R926924 999999 R926858 R926861 9999 9999 R945298 9999 9999 R940328 9999 R926869R926873 9999 R926875 9999 R926876 9999 R926877 9999 R940336 9999 R9268789999 R926882 9999 R926884 9999 R926889 9999 R920400 9999 R920401 9999R920402 9999 R920403 9999 R940342 99 R920409 9999 R940344 9999 R9268889999 R926758 R927024 0.326 99 R927025 0.326 R927026 9999 9999 R9270279999 9999 R927028 0.208 9999 R927029 R927030 0.26 9999 R927031 0.215 99R927032 0.899 R927035 0.583 9999 R927036 R927037 0.233 9999 R927038 1.059999 R927039 1.23 9999 R927040 1.05 9999 R927041 0.788 9999 R927042R935270 R935368 0.082 9999 R935369 0.255 9999 R935370 R935371 0.794 9999R935372 0.06 9999 R935373 0.274 9999 R935374 0.356 9999 R935375 10 9999R935376 R935377 R935378 0.566 9999 R935379 R935380 1.61 99 High DensityBMMC BMMC BMMC BMMC BMMC BMMC Test anti-IgE Ionomycin anti-IgE anti-IgEanti-IgE anti-IgE Compound hexos Hexos. histamine LTC4 TNF-alpha IL-6R008951 R008952 R008953 R008955 R008956 R008958 R067934 R067963 R070153R070790 R070791 R081166 R088814 R088815 R091880 R092788 R908696 R908697R909236 R909237 R909238 <0.22 <0.22 0.521 0.432 <0.22 R909239 R909240R909241 <0.22 <0.22 1.021 0.253 <0.22 R909242 R909243 R909245 R909246R909247 R909248 R909249 R909250 R909251 R909252 R909253 R909254 R920664R920665 R920666 R920668 R920669 R920670 R920671 R920672 R920818 R920819R920820 R920846 R920860 R920861 R920893 R920894 R920910 R920917 R9212180.133 9999 0.203 0.766 0.274 0.100 R921219 0.069 0.058 0.040 0.039 0.009R925734 9999 9999 R925747 3.1 R925755 R925757 R925758 R925760 R925765R925766 R925767 R925768 R925769 R925770 R925771 R925772 R925773 R925774R925775 R925776 R925778 R925779 R925783 R925784 R925785 R925786 R925787R925788 R925790 R925791 R925792 R925794 R925795 R925796 R925797 R925798R925799 R925800 R925801 R925802 R925803 R925804 R925805 R925806 R925807R925808 R925810 R925811 R925812 R925813 R925814 R925815 R925816 R925819R925820 R925821 R925822 R925823 R925824 R925837 R925838 R925839 R925840R925841 R925842 R925843 R925844 R925845 R925846 R925849 R925851 R925852R925853 R925854 R925855 R925856 R925857 R925858 R925859 R925860 R925861R925862 R925863 R925864 R925865 R926016 9999 9999 R926017 1.4 9.6R926018 8.5 9999 R926037 9999 9999 R926038 9999 9999 R926039 9999 9999R926058 9999 9999 R926064 5.9 7.3 R926065 9999 9999 R926068 7.4 8.2R926069 4.5 4.4 R926072 9999 9999 R926086 2.8 7.3 R926108 0.9 9999R926109 0.6 3.2 R926110 1 4.5 R926113 0.65 9999 R926114 9999 9999R926145 2.4 8.8 R926146 1.35 5 R926147 2 7.1 R926206 6.6 8.6 R926209 109.1 R926210 0.6 >10 R926211 3.9 >10 R926212 0.5 5 R926213 R926218 99999999 R926219 2.5 3.2 R926220 9999 9999 R926221 9.9 9999 R926222 99999999 R926223 9999 9999 R926224 9999 9999 R926225 9999 9999 R926228 9999R926229 R926230 R926234 9999 R926237 1.9 R926240 R926241 R926242 R926243R926245 R926248 R926249 R926252 R926253 R926254 R926255 R926256 R926257R926258 R926259 R926319 R926320 R926321 R926325 R926331 R926339 R926340R926341 R926342 R926376 R926386 R926387 R926394 R926395 R926396 R926397R926398 R926399 R926400 R926401 R926402 R926403 R926404 R926405 R926406R926408 R926409 R926411 R926412 R926461 R926467 R926469 R926474 R926475R926476 R926477 R926478 R926479 R926480 R926481 R926482 R926483 R926484R926485 R926486 R926487 R926488 R926489 R926490 R926491 R926492 R926493R926494 R926495 0.056 0.089 0.24 0.077 0.028 R926496 R926497 R926498<0.22 0.515 0.995 0.614 <0.22 R926499 R926500 R926501 R926502 R926503R926504 R926505 <0.22 <0.22 <0.22 <0.22 <0.22 R926506 R926508 0.0860.107 0.162 0.054 0.026 R926509 R926510 R926511 R926514 R926516 R926526R926527 R926528 R926535 R926536 R926555 R926559 R926560 R926562 R926563R926564 R926565 R926566 R926567 R926569 R926571 R926572 R926574 R926576R926579 R926580 R926582 R926583 R926584 R926585 R926586 R926587 R926588R926589 R926591 R926593 R926594 R926595 R926604 R926605 R926614 R926615R926616 R926617 R926620 R926623 R926662 R926663 R926675 R926676 R926680R926681 R926682 R926683 R926688 R926690 R926696 R926698 R926699 R926700R926701 R926702 R926703 R926704 R926705 R926706 R926707 <0.056 <0.0560.39 0.088 <0.056 R926708 R926709 R926710 R926711 R926712 R926713R926714 R926715 R926716 R926717 R926718 R926719 R926720 R926721 R926722R926723 R926724 R926725 R926726 R926727 R926728 R926730 R926731 R926732R926733 R926734 R926735 R926736 R926737 0.075 0.073 0.046 0.068 0.017R926738 R926739 R926740 R926741 0.961 1.025 9999 0.772 0.537 R9267420.041 0.055 0.105 0.053 0.022 R926743 R926744 R926745 R926746 R926747R926748 R926749 R926750 R926751 R926764 R926765 R926766 R926767 R926768R926769 R926770 R926771 R926772 R926773 R926774 R926775 R926776 R926777R926778 R926779 R926780 <0.22 <0.22 0.461 <0.22 <0.22 R926781 R926782<0.22 <0.22 1.461 0.276 <0.22 R926783 R926784 R926785 0.989 0.561 1.4111.312 0.513 R926786 R926787 R926788 R926789 R926790 R926791 0.064 <0.0560.896 0.205 <0.056 R926792 R926793 R926795 R926796 R926797 R926798R926799 R926800 R926801 R926802 R926803 R926804 R926805 R926806 R926807R926808 R926809 R926810 R926811 R926812 R926813 R926814 R926815 R926816R935000 R935001 R935002 R935003 R935004 R935005 R935006 R935016 R935019R935020 R935021 R935023 R935025 R935029 R935075 R935076 R935077 R935114R935117 R935134 R935135 R935136 R935137 R935138 <0.22 <0.22 0.373 0.409<0.22 R935139 R935140 R935141 R935142 R935143 R935144 R935145 R935146R935147 R935148 R935149 R935150 R935151 R935152 R935153 R935154 0.1040.085 0.547 0.131 0.041 R935155 R935156 <0.22 <0.22 0.433 0.22 <0.22R935157 R935158 R935159 R935160 <0.22 0.317 0.876 0.484 <0.22 R935161R935162 R935163 R935164 R935165 R935166 R935167 R935168 R935169 R935170R935171 R935172 R935173 R935174 R935175 R935176 R935177 R935178 R935179R935180 R935181 R935182 R935183 R935184 R935185 R935186 R935187 R935188R935189 R935190 R935191 0.068 0.043 0.213 0.071 0.027 R935192 R9351930.08 0.048 0.312 0.092 0.037 R935194 0.125 0.054 0.493 0.118 0.034R935196 R935197 R935198 R935199 R935202 R935203 R935204 R935205 R935206R935207 R935208 R935209 R935211 R935212 R935213 R935214 R935218 R935219R935220 R940089 R940090 R940095 R940100 R940215 R940216 R940217 R940222R940233 R940235 R940250 R940251 R940253 R940254 R940255 R940256 R940257R940258 R940260 R940261 R940262 R940263 R940264 R940265 0.981 0.3061.211 1.131 0.486 R940266 R940267 R940269 R940270 R940271 R940275R940276 0.136 0.073 0.332 0.251 <0.056 R940277 0.279 0.315 0.625 0.2620.181 R940280 R940281 R940282 R940283 R940284 R940285 R940286 R940287R940288 R940289 R940290 0.255 0.545 0.59 0.246 0.1 R940291 R940292R940293 R940294 R940295 R940296 R940297 R945025 R945032 R945033 R945034R945035 R945036 R945037 R945038 R945040 R945041 R945042 R945043 R945045R945046 R945047 R945048 R945051 R945052 R945053 R945056 R945057 R945060R945061 R945062 R945063 R945064 R945065 R945066 R945067 R945068 R945070R945071 R945096 R945097 R945109 R945110 R945117 R945118 R945124 R945125R945126 R945127 R945128 R945129 R945130 R945131 R945132 R945133 R945134R945135 R945137 R945138 R945139 R945140 R945142 R945144 R945145 R945146R945147 R945148 R945149 R945150 >2 >2 9999 0.709 0.634 R945151 R945152R945153 R945155 R945156 R945157 R945162 R945163 R945164 R945165 R945166R945167 R945168 R945169 R945170 R945171 R945172 R945173 R945175 R950082R950083 R950090 R921302 R950092 R950093 R950100 R950107 R950108 R950109R950120 R950121 R950122 R950123 R950125 R950129 R950130 R950131 R950132R950133 R950134 R950135 R950137 R950138 R950139 R950140 R950141 R950142R950143 R950144 R950145 R950146 R950147 R950148 R950149 R950150 R950151R950152 R950153 R950154 R950155 R950156 R950157 R950158 R950159 R950160R950162 R950163 R950164 R950165 R950166 R950167 R950168 R950169 R950170R950171 R950172 R950173 R950174 R950175 R950176 R950177 R950178 R950179R950180 R950181 R950182 R950183 R950184 R950185 R950186 R950187 R950188R950189 R950190 R950191 <0.22 >2 0.401 <0.22 <0.22 R950192 R950193R950194 R950195 R950196 R950197 R950198 R950199 R950200 R950201 R950202R950203 R950204 R950205 R950206 R950207 <0.22 <0.22 0.288 <0.22 <0.22R950208 R950209 R950210 R950211 R950212 R950213 R950214 R950215 R950216R950217 R950218 R950219 R950220 R950221 R950222 R950223 R950224 R950225R950226 R950227 R950229 R950230 R950231 R950232 R950233 R950234 R950235R950236 R950237 R950238 R950239 R950240 R950241 R950251 R950253 R950254R950255 R908698 R908699 R908700 R908701 R908702 R908703 R908704 R908705R908706 R908707 R908709 R908710 R908711 R908712 R908734 R909255 R909259R909260 R909261 R909263 R909264 R909265 R909266 R909267 R909268 R909290R909292 R909308 R909309 R920394 R920395 R920396 R920397 R920398 R920399R920404 R920405 R920406 R920407 R920408 R920410 R920411 R925745 R926238R926752 R926753 R926754 R926755 R926756 R926757 R926759 R926760 R926761R926762 R926763 R926794 R926826 R926827 R926828 R926829 R926830 R926831R926832 R926833 R926834 R926835 R926836 R926837 R926838 R926839 R926840R926841 R926842 R926843 R926844 R926845 R926846 R926847 R926848 R926851R926855 R926856 R926857 R926859 R926860 R926862 R926863 R926866 R926870R926871 R926874 R926879 R926880 R926881 R926883 R926885 R926886 R926887R926890 R926891 R926892 R926893 R926894 R926895 R926896 R926897 R926898R926899 R926900 R926902 R926903 R926904 R926905 R926906 R926907 R926908R926909 R926913 R926914 R926915 R926916 R926917 R926918 R926919 R926922R926923 R926925 R926926 R926927 R926928 R926929 R926930 R926931 R926932R926933 R926934 R926935 R926936 R926937 R926938 R926939 R926940 R926941R926942 R926943 R926944 R926945 R926946 R926947 R926948 R926949 R926950R926951 R926953 R926954 R926955 R926956 R927016 R927017 R927018 R927019R927020 R927023 R935221 R935222 R935223 R935224 R935225 R935237 R935238R935239 R935240 R935242 R935248 R935249 R935250 R935251 R935252 R935253R935255 R935256 R935258 R935259 R935261 R935262 R935263 R935264 R935266R935267 R935268 R935269 R935271 R935276 R935277 R935278 R935279 R935280R935281 R935286 R935287 R935288 R935289 R935290 R935291 R935292 R935293R935294 R935295 R935296 R935297 R935298 R935299 R935300 R935301 R935302R935303 R935304 R935305 R935306 R935307 R935308 R935309 R935310 R935320R935321 R935322 R935323 R935324 R935336 R935337 R935338 R935339 R935340R935351 R935352 R935353 R935354 R935355 R935356 R935357 R935358 R935359R935360 R935361 R935362 R935363 R935364 R935365 R935366 R935367 R940079R940110 R940299 R940300 R940301 R940304 R940306 R940307 R940308 R940309R940311 R940312 R940314 R940316 R940317 R940318 R940319 R940321 R940323R940337 R940338 R921303 R940345 R940346 R940347 R940348 R940349 R940350R940351 R940352 R940353 R940354 R945236 R945237 R945242 R945263 R921304R945299 R950244 R950245 R950246 R950247 R950261 R950262 R950263 R950264R950265 R950266 R950267 R950290 R950291 R950293 R950294 R950295 R950296R950344 R950345 R950346 R950347 R950348 R950349 R950356 R950368 R950371R950372 R950373 R950374 R950376 R950377 R950378 R950379 R950380 R950381R950382 R950383 R950385 R950386 R950388 R950389 R950391 R950392 R950393R945028 R935241 R940298 R940302 R940303 R940305 R935260 R909258 R940313R940315 R935275 R940320 R940322 R926910 R926911 R926912 R926853 R926852R926854 R926920 R926921 R926924 R926858 R926861 R945298 R940328 R926869R926873 R926875 R926876 R926877 R940336 R926878 R926882 R926884 R926889R920400 R920401 R920402 R920403 R940342 R920409 R940344 R926888 R926758R927024 R927025 R927026 R927027 R927028 R927029 R927030 R927031 R927032R927035 R927036 R927037 R927038 R927039 R927040 R927041 R927042 R935270R935368 R935369 R935370 R935371 R935372 R935373 R935374 R935375 R935376R935377 R935378 R935379 R935380

TABLE 1B CHMC CHMC BMMC BMMC BMMC anti-IgE Ionomycin anti-IgE anti-IgEanti-IgE Compound Tryptase Tryptase Hexos. TNF-alpha IL-6 R908580R908586 9999 R908587 9999 R908591 0.075 R908592 0.05 R908946 0.51 9999R908947 0.496 9999 R908950 0.074 47.5 R908951 0.085 5.48 R908952 0.086.07 R908953 0.084 R908954 0.084 9999 R908955 0.293 R908956 0.34 R9093100.207 9999 R909312 1.759 9999 R909313 0.663 9999 R909314 0.293 9999R909316 0.2 9999 R909317 0.0287 9999 0.002 0.007 0.006 R909318 1.02 9999R909319 0.225 9999 R909320 0.29 9999 R909321 0.163 30 R909322 0.225 99990.24 0.14 0.1 R909323 9999 9999 R926957 1.519 9999 R926958 0.353 9999R926959 0.3 9999 R926960 0.399 9999 R926961 1.2 9999 R926962 0.205 9999R926963 0.155 9999 R926964 0.368 9999 R926965 9999 9999 9999 R9269660.539 9999 R926967 0.259 9999 R926968 0.249 R926969 0.359 9999 R9269700.06 9999 R926971 0.034 9999 R926972 5.29 9999 R926973 0.284 R9269740.293 R926975 0.421 30.2 R926976 0.305 8.3 0.59 0.11 0.25 R926977 0.03599999 R926978 0.995 18 R926979 0.109 23.5 R926980 0.68 5.49 R926981 0.1379999 R926982 0.12 9999 R926983 0.195 9999 R926984 0.167 9999 R9269850.14 4.13 R926986 0.345 R926987 10 R926989 0.199 R926990 11.3 R9269910.436 R926992 8888 R926993 0.689 R926994 0.061 R926995 9.565 9999R927004 0.413 R927005 1.158 R927006 2.142 R927007 5.739 R927008 1.123R927009 4.933 R927010 5.006 R927011 0.464 R927012 3.658 R927013 5.171R927014 0.655 R927015 9999 9999 R927043 0.45 9999 R927044 9999 4.28R927045 0.535 9999 R927046 9999 2.4 R927047 0.168 9999 R927048 0.05 9999R927049 0.11 9999 R927050 0.073 3.29 0.103 0.019 0.011 R927051 0.02412.6 R927052 0.678 R927053 0.671 R927054 9999 R927055 9999 R927056 0.1441.58 R927057 0.37 R927058 12.2 R927059 0.291 R927060 0.222 5.17 R9270610.126 4.72 R927062 15.4 9999 R927063 0.849 9999 R927064 0.212 7.24 0.0051.92 0.819 R927065 0.235 9999 R927066 0.283 15.3 R927067 0.625 22.5R927068 0.89 R927069 0.076 13 1.35 0.93 1.09 R927070 0.054 5.24 R9270710.067 R927072 0.064 R927073 0.0668 R927074 0.072 1.38 R927075 0.057 15.2R927076 0.071 R927077 0.284 8.8 R927078 0.245 R927079 0.599 R9270800.204 R927081 2.27 9999 R927082 0.256 9999 R927083 0.316 19 R9270840.466 9999 R927085 7.43 9999 R927086 0.286 9999 R927087 0.436 9999R927088 0.117 9999 R927089 0.144 9999 R927090 0.102 9999 R927091 0.279999 R927092 0.377 9999 R927093 0.303 9999 R927094 9999 9999 R9270960.402 9999 R927097 0.163 0.847 R927098 1.53 9999 R927099 9999 9999R927100 6.199 9999 R927117 0.614 9999 R927118 0.065 3.49 R927119 1.162R927120 1.018 R927121 0.389 R927122 0.328 R927123 0.087 R927124 0.415R927125 0.255 R927126 5.167 R927127 9999 R927128 1.893 R927129 1.219R927130 1.586 R927131 1.473 R927132 2.756 R927133 0.536 R927134 1.286R927135 0.568 R927136 0.945 R927137 9999.000 R927138 0.463 R9271399999.000 R927140 4.823 R927141 9999 R927142 5.000 R927143 3.998 R9271442.273 R927145 5.022 R927146 1.309 R927147 5.088 R927148 0.097 R9271490.355 R927150 0.708 R927151 0.408 R927152 4.864 R927153 9999.000 R9271544.978 R927155 8888.000 R927156 2.779 R927157 0.072 R927158 2.284 R9271594.830 R927160 8888.000 R927162 5.646 R927163 1.827 R931930 0.361 R9319311.817 R931932 0.511 R931933 0.580 R931934 9999.000 R931935 4.706 R9319360.957 R931936 9999 R931937 9999.000 R931938 0.542 R931939 0.415 R9319401.069 R931941 0.494 R931942 5.665 R931943 9999.000 R931944 0.285 R9319459999.000 R931946 5.594 9999 R931947 2.700 9999 R931948 0.197 R9319490.033 R931950 1.243 R931951 0.017 R931952 0.166 R935381 9999 7.74R935382 9999 0.2 R935383 0.146 9999 R935384 9999 9999 R935385 9999 0.217R935386 0.291 R935389 0.877 R935390 0.544 R935391 0.212 9999 0.25 0.190.55 R935392 0.204 9999 R935393 8888 9999 2.44 1.47 0.52 R935394 9999R935395 0.276 R935396 2.58 R935398 8888 R935399 0.909 R935400 0.502R935401 0.51 R935402 0.216 R935403 0.821 R935404 0.581 R935405 0.389R935406 1.17 R935407 0.393 R935408 0.137 9.94 R935409 1.17 R935410 0.417R935411 9999 R935413 0.085 9999 R935412 0.696 R935414 0.204 R9354150.237 R935416 0.166 R935417 0.417 R935418 0.228 9999 R935419 0.23R935420 0.561 R935421 2.89 R935422 0.326 R935423 0.167 R935424 0.628R935425 8888 R935426 9999 R935427 8888 R935428 1.272 R935429 0.036 9999R935430 0.028 9.3 R935431 0.124 R935432 0.036 8.5 R935433 0.106 16.2R935434 0.308 R935435 0.337 R935436 0.058 R935437 0.082 R935438 0.414 23R935439 R935440 0.176 88 R935441 0.586 R935442 0.701 R935443 8888R935444 0.429 9999 R935445 0.184 11 R935446 0.395 9999 R935447 0.511 4.7R935448 0.111 4.3 R935449 0.372 7.8 R935450 0.494 9999 R935451 9999 9999R935452 0.213 9999 R935453 0.15 9999 R935458 8888 9999 R935459 0.343 4.7R935460 0.748 15.6 R935461 0.134 5.03 R935462 0.364 9999 R935463 0.1769999 R935464 22.4 9999 R935465 0.019 4.22 R935466 0.284 R935467 0.352R935468 0.705 5.37 R935469 0.039 3.79 R935469 0.056 R935470 0.804 4.90R935471 0.481 R935472 1.056 R935473 0.057 R935474 0.474 R935475 0.516R935476 0.639 R935477 0.097 R935478 1.700 R935479 1.355 R935480 4.576R935481 0.114 R935482 0.743 R935483 0.601 R935484 1.252 R935485 0.231R935486 1.845 R935487 3.224 R935488 4.443 R935489 0.185 R935490 1.474R935491 6.873 R935492 26.130 R935493 0.385 R935494 3.063 R935495 1.112R935496 1.952 R935497 0.097 R935498 1.016 R935499 1.207 R935500 1.588R935501 0.305 R935502 1.466 R935503 0.400 R935504 2.777 R935505 0.038R935506 0.375 R935507 0.473 R935508 0.967 R935509 0.086 R935510 0.897R935511 1.165 R935512 2.098 R935513 0.106 R935514 1.662 R935515 2.661R935516 2.800 R935517 0.548 R935518 2.963 R935519 0.074 R935520 0.001R935521 0.186 R935522 1.236 R935523 0.001 R935524 0.249 R935525 1.564R935526 9.126 R935527 0.557 R935528 3.332 R935529 0.245 R935529 9999R935531 9999 R935531 0.871 R935532 9999 R935532 0.110 R935533 9999R935533 0.219 R935534 0.398 5.218 R940355 99 9999 R940356 7.21 9999R940358 0.03 4.3 R940361 0.047 2.2 0.06 0.07 0.1 R940363 0.048 9999R940364 0.046 9999 R940365 8888 9999 R940366 0.037 40 0.03 0.005 0.01R940367 0.117 14.1 R940368 0.025 1.58 R940369 0.023 9999 R940370 S 0.059— R940371 0.316 R940372 0.094 R940373 8888 R940380 0.042 R940381 8888R940382 0.104 R940383 0.064 R940384 1.32 R940385 0.033 R940386 3.42R940387 1.19 R940388 0.049 R940389 0.06 R940390 9999 9999 R940391 0.261R940392 0.145 R940393 5.26 R940394 16.5353 R940395 9999 R940396 22.7164R940397 3.7 R940399 0.051 R940400 0.103 R940401 0.125 R940402 8888R945356 1.17 9999 R945357 9999 9999 R945358 9999 9999 R945360 1.37 9999R945361 2.36 9999 R945362 1.57 9999 R945363 0.687 9999 R945364 1.0029999 R945365 0.257 9999 R945366 0.112 9999 R945367 9999 1.29 R9453689999 1.71 R945369 9999 1.27 R945370 0.522 9999 R945371 0.713 9999R945372 9999 0.923 R945373 9999 R945374 9999 R945375 9999 R945376 9999R945377 1.12 R945378 0.754 R945379 9999 R945380 9999 R945381 9999R945382 9999 R945383 0.985 R945384 0.913 R945385 1.1 R945386 1.39R945387 1.12 R945389 0.0748 9999 R945390 0.118 9999 R945391 0.094 9999R945392 0.085 9999 R945393 1.34 21.7 R945394 1.24 5.61 R945395 1.14 9999R945396 2.24 R945397 0.928 R945398 7 R945399 0.163 9999 R945400 9999R945401 8888 9999 R945402 0.112 R945403 1.7 R945404 0.103 R945405 0.131R945406 8888 R945407 8888 R945408 9999 R945409 9999 R945410 9999 R9454112.86 R945412 0.095 R945413 1.698 R945414 0.038 R945415 0.046 R9454160.053 R945417 2.52082 9999 R945418 8888 9999 R945419 0.125 R945420 0.436R945421 0.371 R945422 0.092 R945423 0.145 R945424 0.188 R945426 0.256R945427 0.279 R945432 0.049 R945433 0.276 R945434 8888 R945439 8888R945440 8888 R945443 0.081 9999 R945444 0.043 9999 R945454 20.6 9999R945455 8888 9999 R945456 8888 R945457 0.188 R945458 8888 R945459 0.038R945460 1.184 R945461 0.803 R945462 1.722 R945463 0.722 R945464 0.943R945465 1.960 R945466 1.885 R945467 1.169 R945470 0.862 R945471 0.035R945472 0.094 R945473 0.104 R945474 0.104 R945475 0.046 R945476 0.293R945477 0.363 R945478 0.153 R945479 0.272 R945480 0.199 R945485 0.850R945486 0.588 R945491 0.465 R945492 0.079 R945493 0.069 R945498 0.0019999 R950405 1.36 9999 R950406 9999 9999 R950407 9999 9999 R950408 99994.82 R950409 9999 3.24 R950410 9999 9999 R950411 9999 4 R950412 0.301R950413 9999 9999 R950414 9999 9999 R950415 5.19 16.3 R950416 2.27R950417 2.16 9999 R950418 1.67 9.09 R950419 3.26 9999 R950420 0.114 9999R950421 0.157 9999 R950422 0.475 6.53 R950423 0.05 9999 R950424 0.2364.28 R950425 1.15 R950426 0.142 30 R950427 1.9 R950428 0.123 21 R9504293.969 R950430 0.239 R950432 2.42 R950433 9999 R950434 1.16 R950436 5.53R950437 0.811 R950438 0.888 R950439 9999 R950440 10.47 R950441 9999R950442 9999 9999 R950443 9999 9999 R950444 1.73 R950445 0.379 R9504460.148 R950447 1.41999 9999 R950448 1.08228 36 R950449 0.668 R950450 1.09R950451 0.07 R950452 0.101 R950453 8888 9999 R950454 8.6351 9999 R9504550.217 R950456 3.78374 4.4 R950457 3.08825 9999 R950458 1.32355 12R950459 0.632 R950460 0.177 R950461 0.142 R950462 9999 R950463 2.46R950464 0.244 R950465 0.351 R950469 9999 9999 R950470 16.1729 9999R950471 50.5397 9999 R950472 6.95156 9999 R950493 1.89 R950494 9999R950495 2.2 R950496 12.4 R950497 8888 R950498 9999 R950499 0.199 R9505001.694 R950501 0.430 R950502 2.496 R950503 2.085 R950504 1.275 R9505059999.000 R950506 9999.000 R950507 0.106 R950508 44.555 9999 R9505090.112 R950510 0.093 R950511 9999.000 R950512 6.611 R950513 7.049 R9505140.244 R950515 0.031 R950516 0.025 R950518 1.405 R950519 6.488 R9505200.397 4.513 R950521 0.145 5.814 R950522 0.123 9999 R950523 0.084 7.728R950524 0.224 5.963 R950525 0.292 14.819

TABLE 2 High Density Toxicity Toxicity CHMC CHMC CHMC CHMC CHMC CHMCToxicity Jurkat Toxicity BJAB high density high density high densityhigh density high density high density Jurkat Cell BJAB Cell hexostryptase histamine LTC4 TNF-alpha IL-13 Light Scat. Titer Glo LightScat. Titer Glo R008951 R008952 R008953 R008955 R008956 R008958 R067934R067963 R070153 R070791 R081166 R088814 R088815 R091880 R092788 99999999 R909241 3.736 R921219 0.124 0.121 0.162 0.034 0.190 0.175 >10 >10R925775 9999 9999 R925778 9999 9999 R925779 >10 9999 R925797 >10 9999R926108 >10 >10 R926109 0.783 0.906 1.827 0.808 1.504 1.664 >10 9999R926110 >10 >10 R921218 0.464 0.647 0.463 0.695 1.752 2.0776 >10 >10R926113 1.448 1.649 1.848 0.468 5.678 3.569 >10 >10 R926146 9999 9999R926210 >10 9999 R926240 10 9999 R926248 >10 9999 R926249 >10 9999R926253 9999 9999 R926256 >10 9999 R926258 9999 9999 R926387 >10 9999R926395 >10 9999 R926396 >10 9999 R926411 8.5 >10 R926486 1.088 1.3131.928 0.834 0.455 R926488 0.521 0.623 0.792 0.201 2.443 1.012 R9264930.889 1.093 1.324 0.474 >2 >4.33 R926494 0.640 >2 9999 0.326 9999R926495 0.100 0.235 0.066 0.241 0.362 0.449 >10 >10 R926496 0.429 0.5330.809 0.414 0.622 R926497 1.106 1.234 1.333 1.876 9999 R926501 >2 >29999 9999 9999 >4.33 >4.33 R926502 >2 >2 >2 1.807 >2 1.513 R926505 4.199R926508 0.170 0.434 0.105 0.505 0.763 >10 >10 R926510 0.921 1.115 1.6670.417 0.686 2.77 R926511 1.183 1.474 1.73 1.307 >2 >4.33 >4.33R926614 >10 >10 >10 6.442 R926696 <1.1 <1.1 <1.1 <1.1 <1.1 1.773 >5.0R926699 <1.1 <1.1 1.44 <1.1 <1.1 1.294 R926700 <1.1 <1.1 <1.1 <1.1 <1.12.053 R926703 1.512 1.947 >2 0.724 >2 R926704 >2 9999 9999 9999 9999R926705 1.007 1.256 0.641 0.494 9999 R926706 >2 9999 9999 1.491 9999R926742 0.104 0.217 0.080 0.385 0.667 9 >10 R926745 >10 >10 R926780 >5.0R926782 >4.33 >4.33 R935075 0.647 1.212 0.443 <0.22 >2 >4.33 >4.33R935154 >4.33 R935156 4.054 R940216 <1.1 <1.1 1.176 <1.1 3.188 3.006R940233 0.577 0.642 0.586 0.118 2.247 1.781 >4.33 >4.33 R945032 0.3570.458 0.439 0.0929 1.082 0.291 R945033 8.151 8.868 >10 5.983 R945071<1.1 <1.1 <1.1 <1.1 <1.1 <1.1 R945128 1.279 1.749 0.547 0.729 >2 NDR945140 0.994 1.112 1.551 1.714 9999 R945142 >2 >2 9999 >2 9999R945150 >4.33 >4.33 R921302 0.682 0.795 1.588 0.514 1.173 1.672 R9501410.567 0.618 0.627 0.201 1.059 0.798 R950207 >4.33

7.7 The 2,4-Pyrimidinediamine Compounds of the Invention SelectivelyInhibit the Upstream IgE Receptor Cascade

To confirm that many of the 2,4-pyrimidinediamine compounds of theinvention exert their inhibitory activity by blocking or inhibiting theearly IgE receptor signal transduction cascade, several of the compoundswere tested in cellular assays for ionomycin-induced degranulation, asdescribed below.

7.7.1 CHMC Low Cell Density Ionomycin Activation: Tryptase Assay

Assays for ionomycin-induced mast cell degranulation were carried out asdescribed for the CHMC Low Density IgE Activation assays (Section 7.5.2,supra), with the exception that during the 1 hour incubation, 6×ionomycin solution [5mM ionomycin (Sigma I-0634) in MeOH (stock) diluted1:416.7 in MT buffer (2 μM final)] was prepared and cells werestimulated by adding 25 μl of the 6× ionomycin solution to theappropriate plates.

7.7.2 Basophil Ionomycin Activation: Histamine Release Assay

Assays for ionomycin-induced basophil cell degranulation were carriedout as described for the Basophil IgE or Dustmite Activation Assay(Section 7.5.5, supra), with the exception that following incubationwith compound, cells were stimulated with 20 μl of 2 μM ionomycin.

7.7.3 Results

The results of the ionomycin-induced degranulation assays, reported asIC50 values (in μM) are provided in TABLE 1, supra. Of the activecompounds tested (i.e., those that inhibit IgE-induced degranulation),the vast majority do not inhibit ionomycin-induced degranulation,confirming that these active compounds selectively inhibit the early (orupstream) IgE receptor signal transduction cascade.

These results were confirmed for certain compounds by measuringanti-IgE-induced and ionomycin-induced calcium ion flux in CHMC cells.In these Ca²⁺ flux tests, 10 μM R921218 and 10 μM R902420 inhibitedanti-IgE-induced Ca²⁺ flux, but had no effect on ionomycin-induced Ca²⁺flux (See FIG. 4).

7.8 The Inhibitory Effect of the 2,4-Pyrimidinediamine Compounds of theInvention is Immediate

To test the immediacy of their inhibitory effect, certain2,4-pyrimidinediamines of the invention were added simultaneously withanti-IgE antibody activator in the cellular assays described above. Allcompounds tested blocked IgE-induced degranulation of CHMC cells to thesame extent as observed when the compounds were pre-incubated with CHMCcells for 10 or 30 min. prior to receptor cross-linking

7.9 Kinetics of Pharmacological Activity In vitro

Compounds R921218, R921302, R921219, R926240, R940277, R926742, R926495,R909243 and R926782 were tested in washout experiments. In theexperiments, CHMC cells were either activated immediately with anti-IgEantibody in the presence of 1.25 μM compound (time zero), or thecompound was washed out followed by activation with anti-IgE antibody at30, 60 or 120 min. The inhibitory activity of these compounds wasgreatly diminished 30 min. after compound removal, indicating thatconstant exposure of mast cells to these compounds is required formaximal inhibition of degranulation The other compounds tested yieldedsimilar results.

7.10 Toxicity: T- and B-Cells

The ability of the compounds of the invention to exert their inhibitoryactivity without being toxic to cells of the immune system wasdemonstrated in cellular assays with B- and T-cells. The protocols forthe assays are provided below.

7.10.1 Jurkat (T-Cell) Toxicity

Dilute Jurkat cells to 2×10⁵ cells/ml in complete RPMI (10%heat-inactivated fetal bovine serum) media and incubate at 37° C., 5%CO₂ for 18 hours. Add 65 ul cells at 7.7×10⁵ cells/ml to a 96-wellV-bottom plate (TC-treated, Costar) containing 65 ul 2× compound (finalvehicle concentration is 0.5% DMSO, 1.5% MeOH). Mix, incubate plates for18-24 hr at 37° C., 5% CO₂. Toxicity was assessed by flow cytometricanalysis of cellular light scatter

7.10.2 BJAB (B-Cell) Toxicity

The B-cell line BJAB was cultured in log phase in RPMI1640+10%heat-inactivated fetal bovine serum, 1× L-glutamine, 1× penicillin, 1×streptavidin and 1× beta-mercaptoethanol at 37° C., 5% CO2. First, BJABswere harvested, spun and resuspended in culture medium to aconcentration of 7.7×10⁵ cells/mL. 65 uL cells were mixed with 65 uLcompound, in duplicate and in the presence of 0.1% DMSO in a V-bottomed96-well tissue culture plate. Cells were incubated with compound atvarious dilutions at 37° C., 5% CO₂. Toxicity was assessed by flowcytometric analysis of cellular light scatter.

7.10.3 Toxicity: Cell Titer Glo Assay

Seed 50 μl cells (1×10⁶/ml) into each well containing 50 μl compound.The final vehicle concentration is 0.5% DMSO, 1.5% MeOH. Shake platesfor 1 minute to mix cells and compound. Incubate plates at 37° C. (5%CO₂) for 18 hours. Next day, harvest 50 μl cells from each well, add to50 μl Cell Titer Glo reagent (Invitrogen). Shake plates for 1 minute.Read on luminometer.

7.10.4 Results

The results of the T- and B-cell toxicity assays, reported as IC₅₀values (in μM), are presented in TABLE 2, supra. With a few exceptions(see TABLE 1), all compounds tested were non-toxic to both B- andT-cells at effective inhibitory concentrations. Assays performed withprimary B-cells yielded similar results.

7.11 The 2,4-Pyrimidine Compounds Are Tolerated In Animals

The ability of the compounds of the invention to exert their inhibitoryactivity at doeses below those exhibiting toxicity in animals wasdemonstrated with compounds R921218, R921219 and R921302.

7.11.1 R921218

R921218 was studied in an extensive program of non-clinical safetystudies that concluded this agent to be well tolerated in both rodentsand non-rodents. To summarize the outcome of toxicology/non-clinicalsafety testing with R921218; this agent produced no dose limitingtoxicity by the intranasal route of administration in non-rodents(rabbits and primates) or by the oral route of administration in rodents(mice and rats) during 14-day repeat-dose toxicity studies at doses manyfold above the anticipated dose expected to produce efficacy in man.There were no adverse findings in a core safety pharmacology battery ofcardiovascular, respiratory and/or central nervous system function.There was no evidence for mutagenic or elastogenic potential in genetictoxicology testing nor were there untoward effects after exposure toskin and eyes. A short discussion of key toxicology studies is provided.

A 14-day repeat-dose intranasal toxicity study in Cynomolgus monkeys wasperformed at doses of 2.1, 4.5 or 6.3 mg/kg/day. In life parametersincluded: clinical observations, body weights, food consumption,ophthalmology, blood pressure, electrocardiography, hematology, clinicalchemistry, urinalysis, immunotoxicological assessment, gross necropsy,organ weights, toxicokinetic assessments and histopathology (includingthe nasal cavity). There were no adverse findings attributed to R921218in any study parameter and the NOAEL (no observed adverse effect level)was considered 6.3 mg/kg/day.

A 14-day repeat-dose intranasal toxicity study in New Zealand Whiterabbits was performed at doses of 1.7, 3.4 or 5.0 mg/kg/day. In lifeparameters included: clinical observations, body weights, foodconsumption, ophthalmology, hematology, clinical chemistry, grossnecropsy, organ weights, toxicokinetic assessments and histopathology(including the nasal cavity). There were no adverse findings attributedto R921218 in any study parameter and the NOAEL (no observed adverseeffect level) was considered 5.0 mg/kg/day.

7.11.2 R921219

In pilot dose finding studies a single dose oral dose of 600 mg/kg wasconsidered a NOEL (no observed effect level) while multiple (7-day)doses of 200 mg/kg/day and above were not tolerated.

In the in vitro Salmonella-Escherichia coli/Mammalian-Microsome ReverseMutation Assay (Ames test), R921219 was found to test positive in testerstrain TA1537, with and without metabolic activation, confirming theresults of an earlier study. R921219 was not found to adversely affectany of the other 4 tester strains. R921219 was not found to possesselastogenic potential when studied in an in vitro chromosomal aberrationassay.

7.11.3 R921302

Several non-GLP pilot toxicity studies have been conducted in rodents.In the mouse an oral dose of 1000 mg/kg was tolerated for up to 7-days.In a 14-day oral toxicity study in the mouse was conducted with doses of100, 300 and 1000 mg/kg. A dose of 1000 mg/kg was not tolerated, while adose of 300 mg/kg promoted evidence for histopathological changes in thevulva. A dose of 100 mg/kg was considered the NOAEL (no observed adverseeffect level) in the study. A 28-day oral toxicity study in the mousewas conducted at doses of 100 mg/kg q.d., 100 mg/kg b.i.d., 300 mg/kgq.d. and 300 mg/kg b.i.d. R921302 was not tolerated at 300 mg/kg q.d. orb.i.d. The lower doses (100 mg/kg q.d. or b.i.d.) appeared to be welltolerated (results of clinical and histopathology are not yet known). Inthe rat oral doses of 50, 150 and 300 mg/kg given for 32 days appearedto be well tolerated (results of clinical and histopathology are not yetknown).

In the in vitro Salmonella-Escherichia coli/Mammalian-Microsome ReverseMutation Assay (Ames test), R921302 was found to test positive in testerstrain TA98 with S9 and TA1537, with and without metabolic activation.R921302 was not found to adversely affect any of the other 3 testerstrains. R921302 was not elastogenic when assessed in an in vitrochromosomal aberration assay.

7.12 The 2,4-Pyrimidinediamine Compounds Are Orally Bioavailable

Over 50 2,4-pyrimidinediamine compounds of the invention were tested fororal bioavailability. For the study, compounds were dissolved in variousvehicles (e.g. PEG 400 solution and CMC suspension) for intravenous andoral dosing in the rats. Following administration of the drug, plasmasamples were obtained and extracted. The plasma concentrations of thecompounds were determined by high performance liquidchromatography/tandem mass spectrometry (LC/MS/MS) methods.Pharmacokinetic analyses were performed based on the plasmaconcentration data. The pharmacokinetic parameters of interest includeClearance (CL), Volume of distribution at steady-state (Vss), terminalhalf-life (t_(1/2)), and oral bioavailability (% F).

These pharmacokinetic studies indicate that many of the2,4-pyrimidinediamine compounds are orally available, with %F up toapproximately 50% (in the range of 0-50%). The half-lives ranged from0.5 to 3 hr. In particular, Compounds R940350, R935372, R935193, R927050and R935391 exhibited good oral bioavailabilities and half-lives inrats. Thus, these studies confirm that these 2,4-pyrimidinediaminecompounds are suitable for oral administration.

7.13 The Compounds Are Effective for the Treatment of Allergies

The in vivo efficacy of compounds R926109, R921218, R921219, R921302,R926495, R926508, R926742, R926745 and R945150 towards allergies wasevaluated in the mouse model of passive cutaneous anaphylaxis (PCA).This model provides a direct measure of IgE-induced degranulation oftissue mast cells. In this model, IgE primed animals are exposed to anallergen challenge, and the change in permeability of dermal vasculaturethat results from histamine release from mast cells is measured bychange in the amount of dye leakage into surrounding tissue. Inhibitionof mediator release by compounds that modulate mast cell degranulationis easily measured by extracting the dye from the tissue.

7.13.1 Study Protocol and Results

In the PCA assay mice are passively sensitized by intradermal injectionwith anti-dinitrophenol (DNP) IgE antibodies (Day −1). At predeterminedtimes animals are treated with the test agent (Day 0). The modulatoryeffect of the agent on cutaneous mast cell degranulation is measuredfollowing intravenous injection of DNP conjugated to human serum albumin(HSA-DNP), together with Evans blue dye. The resulting cross-linking ofthe IgE receptor and subsequent mast cell degranulation-induced increasein vascular permeability is determined by measuring the amount of dyeextravasation into the tissue. Dye is extracted from the tissue byformamide, and the absorbance of this extract is read at 620 nm. Theinhibitory effect of drug treatment is reported as the percentinhibition compared to vehicle treatment, that is, the percent reductionin A₆₂₀.

Two compounds have been tested as positive controls: the histamineantagonist diphenhydramine and the serotonin antagonist cyproheptadine.Both mediators (histamine and serotonin) arc released upon IgE-mediateddegranulation from the mouse mast cell. Both reference compounds inhibitthe PCA response; cyproheptadine was used routinely in subsequentexperiements. Cyproheptadine reproducibly inhibited the PCA response by61% +/−4% (8 mg/kg, i.p., 30 minutes pretreatment time, n=23experiments).

7.13.1.1 Results

A dose-dependent inhibition of the FcεR—mediated vascular leakage wasobserved with increasing doses of R921218, R926109, R921219 andRR921302. These compounds were administered either in a solutionformulation (67% PEG/33% citrate buffer) or an aqueous suspension (1.5%Avicel). These results demonstrate the strong correlation betweencompound plasma levels, in vivo efficacy, and in vitro potency. The mostpotent compound, R921219, was active with circulating exposure levels ofapproximately 10 μg/m1 (68% inhibition at a dose level of 100 mg/kg)compared with R921302, a relatively less potent molecule, which reducedplasma extravasation by 42% at a dose level of 100 mg/kg. Further, thelength of exposure to circulating compound was reflected in the durationof inhibitory activity. R921302, determined to be the most metabolicallystable compound in pharmacokinetics study, inhibited the vascularpermeability for 1-2 hours prior to antigen-induced receptor signaling,where after the efficacy began to decrease. These data are summarized inTABLE 3 and TABLE 4.

TABLE 3 Efficacy of R921218, R926109, R921219 and R921302 in the PCAAssay Pretreat- ment % Plasma Com- time Dose Inhi- level pound RouteVehicle (min) (mg/kg) bition (μg/ml) R921218 PO 67% PEG/33% 10 50 7 3citrate buffer 100 11 4 200 50 18 R926109 PO 67% PEG/33% 15 50 22 N.D.citrate buffer 100 32 200 48 R921219 PO 1.5% 15 30 25 0.4 Avicel/water100 68 4 300 92 11 R921302 PO 1.5% 60 50 35 25 Avicel/water 100 42 38150 56 64 200 93 105

TABLE 4 Duration of action of R921219 and R921302 in the PCA AssayPretreat- % Plasma Dose ment Inhi- level Compound Route Vehicle (mg/kg)time (min) bition (μg/ml) RR921302 PO 1.5% 200 30 89 88 Avicel/ 60 83 53water 120 82 61 240 37 8

Similar in vivo activity was observed with compounds R926495, R926508,R926742, R926745 and R926150, which were able to inhibit the PCAresponse after administration by the oral route in a PEG-basedformulation (data not shown).

7.14 The Compounds Are Effective in the Treatment of Asthma

The efficacy of compounds R921218, R921302, R926495, R926508, R926742and R921219 in the treatment of asthma was demonstrated in the sheepmodel of allergic asthma. Sheep develop bronchoconstriction withinminutes of exposure to inhaled antigen (Ascaris suum), with maximalairflow obstruction during the early allergic response (EAR). Release ofpreformed mast cell mediators is likely responsible for this early phaseof airflow obstruction. In addition to the EAR, the sheep model allowsus to evaluate the effect of our compounds on the late asthmaticreaction (LAR) and non-specific airway hyperresponsiveness (AHR), whichoccur as a result of topical or local administration of allergen to theairway. In the sheep, AHR develops a few hours following antigenchallenge, and can persist for up to 2 weeks. The results describedbelow demonstrate the potential of the tested compounds to inhibit acascade of events that may be a result of release of cytokines from themast cell.

7.14.1 Study Protocol

In the sheep model of allergic asthma, sheep are administered aerosolsof test article via an endotracheal tube, followed by an aerosolchallenge with antigen extracted from the roundworm, Ascaris suum, towhich the sheep are naturally allergic. Allergen challenge leads todirect bronchoconstriction (both EAR and LAR) and a persistentnon-specific AHR. These three characteristics are similar to those seenin human allergic asthmatics. The activity of the test agent isdetermined by changes in the lung resistance (R_(L)), which iscalculated from measurements of transpulmonary pressure, flow, andrespiratory volume. The historical control data obtained from the samesheep following saline treatment compared with an allergen challengeshow that a sharp increase of R_(L) occurs during the EAR and persistsfor approximately 2-3 hours following allergen challenge. The LAR is aless pronounced increase in R_(L), which starts approximately 5-6 hoursfollowing allergen challenge and is resolved by 8 hours post-challenge.Twenty-four hours after the challenge, a dose response to carbachol ismeasured to determine the AHR, which is expressed as the dose ofcarbachol required to increase R_(L) by 400% over baseline. (Thismeasurement is referred to as the provocative concentration of carbacholthat elicits a 400% increase in RL over baseline (PC₄₀₀). The data arecompared to historical control data for the same individual whenadministered a saline control aerosol and challenged with Ascaris suum.

7.14.2 Result

All the compounds tested showed inhibitory effects in the LAR and theAHR, and several of these agents inhibited the EAR as well. The optimalresponse for each compound in a series of studies to evaluate activityat several pretreatment times and using several different solution andsuspension formulations are shown in TABLE 5. The efficacy of R921218 onthe EAR appeared to be dependent on the formulation, with the greatesteffect seen at 30 mg/sheep administered as a solution aerosol in 10%ethanol. R926495, R926742, R926508 and R921219, administered in fourdifferent sheep at 45 mg/sheep in an aqueous suspension 60 minutes priorto allergen challenge, demonstrate that the LAR and AHR is blocked. Inaddition to these late parameters, the EAR was greatly reduced bytreatment with R921219, R926508 or R926495. The efficacy of RR921302 wasinvestigated using a 45%PEG400/55% citrate buffer vehicle. Under theseconditions, R921302, administered at 30 mg/sheep 60 minutes prior tochallenge, blocked the LAR and AHR, and EAR was unaffected.

These data clearly demonstrate that these compounds are able to blockthe asthmatic responses in allergic sheep. All compounds inhibited theAHR and LAR significantly when compared to the historical control. TheEAR was significantly inhibited by R921219, R926508 and R926495 (54%,21% and 33% respectively). In contrast, R921218, R921302 and R926742failed to inhibit the EAR when administered in an aqueous suspension.

TABLE 5 Efficacy Of Exemplary Compounds In A Sheep Model Of AllergicAsthma Dose Pretreatment EAR (% LAR (% AHR (% Compound (mg/sheep) time(min) Vehicle inhibition) inhibition) inhibition) R921218 30 15 10%ethanol 66 78 101 R926742 45 60 Aqueous suspension −19 87 94 R926495 4560 33 85 41 R926508 45 60 21 90 88 R921219 45 60 56 75 90 RR921302 30 6045% PEG400/55% citrate −28 86 82 buffer

7.15 The Compounds Are Effective In The Treatment of Asthma

The efficacy of compounds R921304 and R921219 in the treatment of asthmawas also demonstrated in a mouse model of allergic asthma.

7.15.1 Study Protocol

Mice are sensitized to ovalbumin (chicken protein) in the presence of anadjuvant (Alum) by the intraperitoneal route on day 0 and day 7. Oneweek later, mice are challenged intranasally with ovalbumin on Days 14,15 and 16 (more stringent model) or on Day 14 (less stringent model).This sensitization and challenge regimen leads to airwayhyperresponsiveness and inflammation in the lungs, which are twodominant characteristics of human allergic asthma. In the mouse model,the in vivo airway responses are measured using a whole bodyplethysmograph which determines the PENH (enhanced Pause, BuxcoElectronics). The PENH is a dimensionless value comprised of the peakinspiratory flow (PIF), peak expiratory flow (PEF), time of inspiration,time of expiration and relaxation time, and is considered a validatedparameter of airway responsiveness. Responses to allergen challenge(OVA) are compared with animals challenged with saline only. Twenty-fourhours after challenge, mice are exposed to increasing doses ofmethacholine (muscarinic receptor agonist) which results in smoothmuscle contraction. The ovalbumin-challenged mice demonstrate asignificant airway hyperresponsiveness to methacholine when compared tothe saline challenged mice. In addition, a cellular infiltrate in theairway is observed in ovalbumin challenged mice when compared with thesaline challenged mice. This cellular infiltrate is mainly characterizedby eosinophils, but a smaller influx of neutrophils and mononuclearcells is also present.

The use of this model for the evaluation of small molecule inhibitors ofmast cell degranulation has been validated is several ways. First, usingmast cell deficient mice (W/W^(v)) it has been shown that theovalbumin-induced responses are dependent upon the presence of mastcells. In the mast cell deficient mice, ovalbumin sensitization andchallenge did not result in airway hyperresponsiveness and eosinophilinflux. Second, the mast cell stabilizer, Cromolyn, was able to blockthe ovalbumin-induced airway hyperresponsiveness and inflammation (datanot shown). The use of this model to evaluate compounds for thetreatment of asthmatic responses that may be mediated by mechanismsother than mast cell stablization, is further supported by theinhibitory effect of the steroids, dexamethasone and budesonide, onmethacoline-induced bronchocontriction.

7.15.2 Results

The efficacy of R921304 was evaluated by intranasal administration on 10consecutive days, from Day 7 through Day 16, at a dose level of 20mg/kg, with the last 3 doses administered 30 minutes prior to eithersaline or ovalbumin challenge. R921304 was able to inhibit theovalbumin-induced airway hyperresponsiveness to methacholine whencompared to the vehicle treated mice.

In a less stringent protocol, in which the mice were challenged withovalbumin only once on Day 14, R921219 administered subcutaneously at 70mg/kg in 67% PEG400/33% citrate buffer 30 minutes prior to saline orovalbumin challenge, demonstrates that R921219 completely blocked theovalbumin-induced airway hyperresponsiveness and cellular influx.

These results clearly demonstrate that R921219 and R921304 areefficacious in inhibiting the airway responses in a mouse model ofallergic asthma.

7.16 2,4-Pyrimidinediamine Compounds Inhibit Phosphorylation of ProteinsDownstream of Syk Kinase in Activated Mast Cells

The inhibitory effect of the 2,4-pyrimidinediamine compounds on thephosphorylation of proteins downstream of Syk kinase was tested withcompounds R921218, R218219 and R921304 in IgE receptor-activiated BMMCcells.

For the assay, BMMC cells were incubated in the presence of varyingconcentrations of test compound (0.08 μM, 0.4 μM, 2 μM and 10 μM) for 1hr at 37° C. The cells were then stimulated with anti-IgE antibody aspreviously described. After 10 min, the cells were lysed and thecellular proteins separated by electrophoresis (SDS PAGE).

Following electrophoresis, the phosphorylation of the proteins indicatedin FIGS. 7, 10 and 11A-D were assessed by immunoblot. Antibodies werepurchased from Cell Signaling Technology, Beverley, Mass.

Referring to FIGS. 7, 10 and 11A-D, the indicated compounds testedinhibited phosphorylation of proteins downstream of Syk, but notupstream of Syk, in the IgE receptor signaling cascade, confirming boththat the compounds inhibit upstream IgE induced degranulation, and thatthe compounds exhert their inhibitory activity by inhibiting Syk kinase.

7.17 2,4-Pyrimidinediamine Compounds Inhibit Syk Kinase in BiochemicalAssays

Several 2,4-pyrimidinediamine compounds were tested for the ability toinhibit Syk kinase catalyzed phosphorylation of a peptide substrate in abiochemical fluorescenced polarization assay with isolated Syk kinase.In this experiment, Compounds were diluted to 1% DMSO in kinase buffer(20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2 mM MnCl₂, 1 mM DTT, 0.1 mg/mLacetylated Bovine Gamma Globulin). Compound in 1% DMSO (0.2% DMSO final)was mixed with ATP/substrate solution at room temperature. Syk kinase(Upstate, Lake Placid NY) was added to a final reaction volume of 20 uL,and the reaction was incubated for 30 minutes at room temperature. Finalenzyme reaction conditions were 20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2 mMMnCl₂, 1 mM DTT, 0.1 mg/mL acetylated Bovine Gamma Globulin, 0.125 ngSyk, 4 uM ATP, 2.5 uM peptide substrate (biotin-EQEDEPEGDYEEVLE-CONH2,SynPep Corporation). EDTA (10 mM final)/anti-phosphotyrosine antibody(1× final)/fluorescent phosphopeptide tracer (0.5× final) was added inFP Dilution Buffer to stop the reaction for a total volume of 40 uLaccording to manufacturer's instructions (PanVera Corporation) The platewas incubated for 30 minutes in the dark at room temperature. Plateswere read on a Polarion fluorescence polarization plate reader (Tecan).Data were converted to amount of phosphopeptide present using acalibration curve generated by competition with the phosphopeptidecompetitor provided in the Tyrosine Kinase Assay Kit, Green (PanVeraCorporation)

The results of the assay are shown in TABLE 6, below:

TABLE 6 SYK Kinase IC50 Compound (in μM) R908701 0.022 R908702 0.038R908712 0.024 R908952 0.041 R908953 0.017 R908956 1.178 R909236 2.071R921219 0.041 R909268 0.125 R909309 0.09 R909317 0.008 R909321 0.104R909322 0.141 R920410 0.187 R921218 0.254 R926242 1.81 R926252 9999R926321 5049 R926500 0.929 R926501 0.193 R926502 0.217 R926505 0.07R926508 0.097 R926562 9999 R926594 0.771 R926715 0.534 R926742 0.076R926745 0.093 R926753 0.108 R926757 0.51 R926763 0.024 R926780 0.107R926782 0.117 R926791 0.207 R926797 9999 R926798 9999 R926813 0.405R926816 0.062 R926834 0.292 R926839 0.055 R926891 0.116 R926931 0.255R926946 10.218 R926949 0.076 R926953 3.05 R926956 0.38 R926968 0.235R926970 0.057 R926971 0.008 R926975 0.767 R926976 0.421 R926977 0.007R926979 0.013 R926981 0.01 R926982 0.028 R926983 0.012 R926984 0.459R926985 0.203 R926989 0.228 R927016 0.954 R927017 2.351 R927020 9999R927042 0.051 R927048 0.002 R927049 0.004 R927050 0.114 R927051 0.01R927056 0.473 R927060 0.62 R927061 0.158 R927064 0.466 R927069 0.111R927077 0.602 R927078 0.222 R927080 0.254 R927082 0.312 R927083 0.449R935138 0.229 R935189 0.354 R935190 0.047 R935191 0.045 R935193 0.11R935194 0.169 R935196 0.266 R935198 0.2 R935202 0.035 R935237 0.046R935293 0.047 R935302 0.027 R935304 0.042 R935307 0.057 R935309 0.098R935310 0.206 R935366 0.38 R935372 0.205 R935375 2.8 R935391 0.223R935393 0.45 R935413 0.195 R935414 0.152 R935416 0.196 R935418 0.558R935431 0.132 R935432 0.05 R935433 0.07 R935436 0.064 R935437 0.127R940233 0.151 R940255 0.771 R940256 3.211 R940269 0.685 R940275 0.734R940276 0.127 R940277 0.214 R940290 0.187 R940323 0.05 R940338 0.028R921303 0.003 R940346 0.11 R940347 0.038 R940350 0.121 R940351 0.25R940352 0.13 R940353 0.325 R940358 0.023 R940361 0.069 R940363 0.006R940364 0.001 R940366 0.003 R940367 0.013 R940368 0.001 R940369 0.043R940370 0.069 R940371 3.643 R940372 0.253 R940373 9999 R940376 0.067R940380 0.029 R940381 4999.846 R940382 0.144 R940384 9999 R940386 19.49R940387 9999 R940388 0.268 R940389 0.053 R940390 9999 R945071 0.43R945140 0.611 R945142 2.007 R945144 0.612 R945157 1.762 R921304 0.017R945299 0.022 R945365 0.465 R945366 0.059 R945369 1.85 R945370 1.05R945371 1.3 R945385 2.12 R945389 0.035 R945390 0.009 R945391 0.01R945392 0.014 R945398 0.182 R945399 0.166 R945400 17.925 R945401 0.007R945402 0.418 R945402 0.418 R945404 9999 R945405 0.168 R945407 9999R945412 0.308 R945413 9999 R945416 0.515 R945417 9999 R945418 9999R945419 0.127 R945422 0.087 R945423 0.273 R945424 0.665 R945426 0.301R945427 0.479 R945432 4444.247 R945433 0.431 R945434 9999 R921302 0.268R950349 0.033 R950367 0.341 R950368 0.011 R950373 0.067 R950428 0.127R950430 0.15 R950431 9999 R950440 9999 R950466 1.81 R950467 9999 R9504689999 R950473 19.49 R950474 9999 R950475 9999 R950476 9999 R940376 0.067R940380 0.029

These data demonstrate that all of the compounds tested, except forR945142 and R909236 inhibit Syk kinase phosphorylation with IC₅₀s in thesubmicromolar range. All compounds tested inhibit Syk kinasephosphorylation with IC₅₀s in the micromolar range.

7.18 The Compounds Are Effective for the Treatment of Autoimmunity

The in vivo efficacy of certain 2,4-pyrimidinediamine compounds towardsautoimmune diseases was evaluated in the reverse passive Arthusreaction, an acute model of antigen-antibody mediated tissue injury, andin several disease models of autoimmunity and inflammation. These modelsare similar in that antibody to a specific antigen mediates immunecomplex-triggered (IC-triggered) inflammatory disease and subsequenttissue destruction. IC deposition at specific anatomic sites (centralnervous system (CNS) for experimental autoimmune encephalomyelitis (EAE)and synovium for collagen-induced arthritis (CIA)) leads to activationof cells expressing surface FcγR and FcεR, notably mast cells,macrophages, and neutrophils, which results in cytokine release, andneutrophil chemotaxis. Activation of the inflammatory response isresponsible for downstream effector responses, including edema,hemorrhage, neutrophil infiltration, and release of pro-inflammatorymediators. The consequences of these IC-triggered events are difficultto identify in autoimmune disorders; nonetheless, many investigatorshave demonstrated that inhibition of the FcγR signaling pathway in theseanimal models has resulted in a significant reduction in disease onsetand severity.

7.18.1 The Compounds Are Effective In Mouse Arthus Reaction

The in vivo efficacy of compounds R921302, R926891, R940323, R940347,and R921303 to inhibit the 1C-triggered inflammatory cascade wasdemonstrated in a mouse model of Reverse Passive Arthus Reaction (RPAreaction).

7.18.1.1 Model

Immune complex (IC)-mediated acute inflammatory tissue injury isimplicated in a variety of human autoimmune diseases, includingvasculitis syndrome, sick serum syndrome, systemic lupus erythematosus(SLE), rheumatoid arthritis, Goodpasture's syndrome, andglomerulonephritis. The classical experimental model for IC-mediatedtissue injury is the reverse passive Arthus reaction. The RPA reactionmodel is a convenient in vivo method to study localized inflammation,induced by ICs, without systemic effects. Intradermal injection ofantibodies (Abs) specific to chicken egg albumin (rabbit anti-OVA IgG),followed by intravenous (IV) injection of antigens (Ags), specificallychicken egg albumin (ovalbumin, OVA), causes perivascular deposition ofICs and a rapid inflammatory response characterized by edema, neutrophilinfiltration and hemorrhage at the injection sites. Aspects of the mouseRPA reaction model resemble the inflammatory response of patients withrheumatoid arthritis, SLE and glomerulonephritis.

7.18.1.2 Study Protocol

In this model system, test compounds are administered at severaltimepoints prior to administration of Abs and Ags. A solution of rabbitanti-OVA IgG (50 μg in 25 μl/mouse) is injected intradermally, andimmediately following is an intravenous injection of chicken egg albumin(20 mg/kg of body weight) in a solution containing 1% Evans blue dye.The degree of edema and hemorrhage is measured in the dorsal skin ofC57BL/6 mice using the Evan's Blue dye as an indicator of local tissuedamage. Purified polyclonal rabbit IgG is used as a control.

Pretreatment time, in which the test compounds are administered prior toAb/Ag challenge, depends on the pharmacokinetic (PK) properties of eachindividual compound. Four hours after induction of Arthus reaction, miceare euthanized, and tissues are harvested for assessment of edema. Thismodel system allows us to rapidly screen the in vivo activity of manyinhibitors.

7.18.1.3 Results

All compounds tested were administered by the oral route.

R921302, when administered at a dose level of 50 mg/kg, 100 mg/kg, and200 mg/kg 60 minutes prior to Ab/Ag challenge in C57B16 mice, showeddose-dependent inhibition of edema formation (49.9%, 93.2%, and 99.1%,respectively). Furthermore,

R921302 showed not only a prophylactic inhibition of edema, but alsotherapeutic efficacy in which the edema was inhibited by 77.5% when thecompound was administered 30 minutes post-challenge at a dose level of100 mg/kg.

R940323 and R926891 showed the efficacy of edema inhibition by 32.4% and54.9%, respectively, when administered at 200 mg/kg, 60 minutes prior tochallenge. These compounds are much less bioavailable when administeredorally, and systemic exposure levels were approximately 50-fold lessthat that seen with R921302 (data not shown). R940347 inhibited edema by89% when administered at a dose level of 100 mg/kg, 2 hours prior tochallenge.

Compound R921303 showed 100%, 100%, and 93.6%, inhibition of edemaformation when administered at a dose level of 200 mg/kg and apretreatment time of 30, 60, and 120 minutes, respectively). Thecompound also demonstrated a dose-dependent inhibition of 65.4%, 81.2%and 100%, at doses of 50 mg/kg, 100 mg/kg and 200 mg/kg, respectively.Results for the compounds tested are summarized in Table 7.

TABLE 7 Plasma % inhibition Concentration ± to vehicle SEM (ng/ml)control Exposure = Compound Dosage Pretreatment Edema Size ±Pretreatment Name (mg/kg) Time (hrs) SEM Time + 4 hours R921302 100 0.589.44 ± 4.8  25200 ± 3910 100 1  82.1 ± 10.9 N/A 50 1 50.0 ± 6.4 1149 ±172 100 1 92.3 ± 4.2 2072 ± 447 200 1 99.1 ± 0.9  4789 ± 1182 R940323200 0.5  5.5 ± 9.3 2333 ± 618 1  32.4 ± 13.0  878 ± 235 2  26.9 ± 11.2 892 ± 434 R926891 200 0.5 44.8 ± 3.0 163 ± 70 1 46.2 ± 4.1 37.2 ± 8  1.5  28.1 ± 10.6 58.6 ± 19  R921303 200 0.5 100 ± 0  3703 ± 785 1 100 ±0  2653 ± 833 2 93.3 ± 4.4 2678 ± 496 50 1  64.1 ± 13.3  430 ± 115 100 180.5 ± 9.8  983 ± 180 200 1 100 ± 0   2361 ± 1224 R935372 100 0.5 −0.6 ±6.2 0.6 ± 1  1 23.5 ± 7.4 4.2 ± 4  2  −4.4 ± 17.7 52.65 ± 39   R920410100 1  42.6 ± 15.1 1216 ± 239 R927050 100 0.5 −0.3 ± 6.6  619 ± 130 1 14.9 ± 20.5  837 ± 104 2 64.0 ± 8.9 557 ± 78 R940350 100 0.5 −15.6 ±27.2 176 ± 58 1  53.2 ± 15.1 129 ± 55 2  38.9 ± 24.3  96 ± 28 R940347100 0.5  36.7 ± 22.4 1596 ± 485 1 48.2 ± 5.7 3014 ± 590 2 88.9 ± 9.11992 ± 247 R940363 100 0.5 −16.4 ± 10.9  32 ± 10 1  67.6 ± 12.1 42 ± 5 2 52.3 ± 22.7  37 ± 18 R927050 100 1  7 ± 19 1018 ± 189 R927070 50 1  56± 15 1755 ± 310 100 1  61 ± 14 2851 ± 712 R940363 100 1 61 ± 8 625 ± 60R935429 100 1 85 ± 5 401 ± 96 R927070 50 1.5  31.1 ± 17.29 1077 ± 296100 1.5 55.5 ± 7.7  4095 ± 1187 R935429 50 1.5  −5.1 ± 14.9 164 ± 89 1001.5  67.1 ± 13.8  206 ± 115 R935429 100 0  −2.8 ± 14.8 NA 100 1 34.08 ±7.9  NA 100 2 55.5 ± 7.9 NA 100 4  35.0 ± 11.4 NA R927087 50 1.5 −10.4 ±14.4 26.9 ± 8.0 100 1.5  28.7 ± 16.6  28.7 ± 10.8 R935451 50 1.5 74.9 ±7.5  385.0 ± 149.4 100 1.5 77.1 ± 8.0 1459.0 ± 444.4 R935451 10 1.5−14.4 ± 13.3 14.4 ± 1.8 30 1.5 −30.6 ± 15.4  78.0 ± 32.0 R940388 100 1.575.0 ± 6.2 44.2 ± 8.9 R921302 50 1 49.9 1.1 100 1 93.2 2.1 200 1 99.14.8 R940323 200 1 32.4 0.9 R926891 200 1 54.9  0.04 R940347 100 1 48 nd* 100 2 89 nd R921303 50 1 65.4 0.4 100 1 81.2  0.98 200 1 100 2.4*nd = not determined

7.18.2 The Compounds are Effective in Mouse Collagen Antibody InducedArthritis Model

The in vivo efficacy of compound R921302 towards autoimmune diseases wasdemonstrated a mouse model of collagen antibody-induced arthritis(CAIA).

7.18.2.1 Model

Collagen-induced arthritis (CIA) in rodents is frequently used as one ofthe experimental models for IC-mediated tissue injury. Administration oftype II collagen into mice or rats results in an immune reaction thatcharacteristically involves inflammatory destruction of cartilage andbone of the distal joints with concomitant swelling of surroundingtissues. CIA is commonly used to evaluate compounds that might be ofpotential use as drugs for treatment of rheumatoid arthritis and otherchronic inflammatory conditions.

In recent years, a new technique emerged in CIA modeling, in which theanti-type II collagen antibodies are applied to induce anantibody-mediated CIA. The advantages of the method are: Short time forinduction of disease (developing within 24-48 hrs after an intravenous(IV) injection of antibodies); arthritis is inducible in bothCIA-susceptible and CIA-resistant mouse strains; and the procedure isideal for rapid screening of anti-inflammatory therapeutic agents.

Arthrogen-CIA® Arthritis-inducing Monoclonal Antibody Cocktail (ChemiconInternational Inc.) is administered intravenously to Balb/c mice(2mg/mouse) on Day 0. Forty-eight hours later, 100 μl of LPS (25 μg) isinjected intraperitoneally. On Day 4, toes may appear swollen. By Day 5,one or two paws (particular the hind legs) begin to appear red andswollen. On Day 6, and thereafter, red and swollen paws will remain forat least 1-2 weeks. During the study, the clinical signs of inflammationare scored to evaluate the intensity of edema in the paws. The severityof arthritis is recorded as the sum score of both hind paws for eachanimal (possible maximum score of 8). The degree of inflammation withinvolved paws is evaluated by measurement of diameter of the paws. Bodyweight changes are monitored.

Animals are treated at the time of induction of arthritis, beginning onDay 0. Test compounds and control compounds are administered once a day(q.d.) or twice a day (b.i.d.), via per os (PO), depending on previouslyestablished PK profiles.

At the end of the study (1-2 weeks after induction of arthritis), miceare euthanized and the paws are transected at the distal tibia using aguillotine and weighed. The mean±standard error of the mean (SEM) foreach group is determined each day from individual animal clinicalscores, and hind paw weights for each experimental group are calculatedand recorded at study termination. Histopathological evaluation of pawsare obtained.

7.18.2.2 Results

Administration of R921302 significantly suppressed the development ofarthritis and the severity of the disease (p<0.005), as shown by thechanges in mean daily arthritis clinical scores (FIG. 12). The meandaily arthritic scores, from day 4 to 14, in treatment group werereduced between 71 to 92% comparing to that of vehicle control group.The degree of paw inflammation, by measurement of the paw weight, wasreduced in animals treated with R921302 compared with the vehiclecontrol group (FIG. 13). At the end of study, the degree of swelling wasevaluated by measuring the weight of paws, which is indicated by a 99.9%reduction in group treated with R921302 compared with mean paw weight ofthe vehicle control group (p<0.002).

Histopathological evaluation of the resected paws revealed a markedsynovitis consistent with CIA. Marked lesions were noted in animalstreated with saline or vehicle; while lesions of lesser severity werefound in R921302 treatment group. The joints were thickened with markedproliferation of the synovium. There is an increase in fibroblasts witha dense infiltration of neutrophils, lymphocytes, monocytes, macrophagesand plasma cells. There is vascular proliferation with congestion,hemorrhage and edema. Pannus formation was present in the joint spaceand there was cartilage destruction. In drug treated group, the jointswere close to normal or showed limited inflammation but withoutcartilage involvement.

TABLE 8 Group Average Histopathological Score (0-15) Treatment Averagetotal score ± SD Saline control 9.8 ± 2.1 Vehicle control 9.3 ± 4.5R921302 (100 mg/kg), twice daily 5.1 ± 1.9 Naive 0.0 ± 0.0

Arthritic clinical scores and paw edema were reduced by an average of20% in animals treated with R050 twice daily at a dose level of 100mg/kg compared with untreated control (vehicle, p=0.1). Paw edema wasinhibited by approximately 26% compared with untreated control(vehicle), by measurement of hind paw thickness (p=0.1). R050 did notexhibit arthritis at a dose level of 30 mg/kg.

R070, a salt form of R050, administered at dose levels of 50 or 100mg/kg twice daily inhibited clinical disease by an average of 39.75%(p<0.0002) or 35.28% (p<0.0004) inhibition, respectively, compared withuntreated control (vehicle). Paw thickness was reduced by approximately50%.

R429, salt of R363, administered twice daily at 50 or 100 mg/kg showedan average of 23.81% (p<0.05) or 20.82% (p=0.05) inhibition of arthriticclinical scores, respectively, compared with untreated control(vehicle). Likewise, paw thickness was reduced.

R347 did not affect arthritic scores at the dose levels tested (30and100 mg/kg twice daily).

7.18.3 The Compounds Are Effective In Rat Collagen-Induced Arthritis

The in vivo efficacy of compound R921302 towards autoimmune diseases wasdemonstrated in a rat model of collagen-induced arthritis (CIA).

7.18.3.1 Model Description

Rheumatoid arthritis (RA) is characterized by chronic joint inflammationeventually leading to irreversible cartilage destruction. IgG-containingIC are abundant in the synovial tissue of patients with RA. While it isstill debated what role these complexes play in the etiology andpathology of the disease, IC communicate with the hematopoetic cells viathe FcγR.

CIA is a widely accepted animal model of RA that results in chronicinflammatory synovitis characterized by pannus formation and jointdegradation. In this model, intradermal immunization with native type IIcollagen, emulsified with incomplete Freund's adjuvant, results in aninflammatory polyarthritis within 10 or 11 days and subsequent jointdestruction in 3 to 4 weeks.

7.18.3.2 Study Protocol

Syngeneic LOU rats were immunized with native type II collagen on Day 0,and efficacy of R921302 was evaluated in a prevention regimen and atreatment regimen. In the prevention protocol, either vehicle or variousdoses of R921302 were administered via oral gavage starting on day ofimmunization (Day 0). In the treatment protocol, after clinical signs ofarthritis developed on Day 10, treatment with R921302 was initiated (300mg/kg by oral gavage, qd) and continued until sacrifice on Day 28. Inboth protocols, clinical scores were obtained daily, and body weightsare measured twice weekly. At Day 28, radiographic scores were obtained,and scrum levels of collagen II antibody were measured by ELISA.

7.18.3.3 Results

By 10 days after immunization, rats developed clinical CIA, as evidencedby an increase in their arthritis scores (FIG. 14). The mean arthriticscore gradually increased in the rats treated with vehicle alone afterDay 10, and by Day 28 the mean clinical score reached 6.75±0.57. Meanclinical scores in animals treated from the day of immunization (Day 0)with the high dose of R921302 (300 mg/kg/day) were significantly reduced(p<0.01) on Days 10-28 compared with vehicle controls. In the ratstreated with 300 mg/kg R921302 at disease onset, there was asignificantly lower arthritis score beginning on Day 16, and thisdifference was observed until the end of the study on Day 28. Blindedradiographic scores (scale 0-6) obtained on Day 28 of CIA were 4.8±0.056in the vehicle group compared with 2.5±0.0.16, 2.4±0.006, and 0.13±0.000001 in animals treated once daily with 75, 150, and 300 mg/kg/day,respectively, in a prevention regimen, and 0.45±0.031 in animals treatedonce daily with 300 mg/kg/day at onset of disease. R921302 treatment at300 mg/kg/day, either prophylactically (at immunization) or afterdisease onset precluded the development of erosions and reduced softtissue swelling. Similarly, R921302 treatment resulted in markedreduction of serum anti-collagen II antibody (data not shown).

7.18.4 The Compounds Are Effective In Mouse Experimental AutoimmuneEncephalomyelitis

The in vivo efficacy of compound R921302 towards autoimmune diseases wasdemonstrated in a mouse model of experimental autoimmuneencephalomyelitis (EAE) 7.18.4.1 Model Description

EAE is a useful model for multiple sclerosis (MS), an autoimmune diseaseof the CNS that is caused by immune-cell infiltration of the CNS whitematter. Inflammation and subsequent destruction of myelin causeprogressive paralysis. Like the human disease, EAE is associated withperipheral activation of T cells autoreactive with myelin proteins, suchas myelin basic protein (MBP), proteolipid protein (PLP), or myelinoligodendrocyte protein (MOG). Activated neuroantigen-specific T cellspass the blood-brain barrier, leading to focal mononuclear cellinfiltration and demyelination. EAE can be induced in susceptible mousestrains by immunization with myelin-specific proteins in combinationwith adjuvant. In the SJL mouse model used in these studies, hind limband tail paralysis is apparent by Day 10 after immunization, the peak ofdisease severity is observed between Days 10 and 14, and a cycle ofpartial spontaneous remission followed by relapse can be observed up toDay 35. The results described below demonstrate the potential of thetest agent (R921302) to suppress disease severity and prevent relapse ofdisease symptoms that may be the result of FcγR-mediated cytokinerelease from immune cells.

7.18.4.2 Study Protocol

In the SJL murine model of EAE, each mouse is sensitized with PLP/CFA.(150 PLP139-151 with 200 μg CFA in 0.05 ml of homogenate on four sitesof hind flank for a total of 0.2 ml emulsion is used to induce EAE). Ina suppression protocol, either vehicle or various doses of R921302 areadministered via oral gavage starting on the day of immunization (Day0). In a treatment protocol, at onset of disease, animals are separatedto achieve groups with a similar mean clinical score at onset andadministered vehicle or various dose frequencies of test articles viaoral gavage. In both protocols, clinical scores are monitored daily, andbody weights are measured twice weekly.

7.18.4.3 Results

By 10 days after PLP immunization, SJL mice developed clinical EAE, asevidenced by an increase in their mean clinical scores (FIG. 15). Theparalytic score gradually increased in the animals treated with vehicleonly from the day of immunization (Day 0), and by Day 14 the mean scorereached a peak of 5.1 +0.3. At disease peak (Day 14), the mean clinicalscore in animals treated with either 100 mg/kg daily or 100 mg/kg twicedaily was significantly reduced (p<0.05, 4.3+1.3 and 4.3+1.4,respectively). By Day 16, all animals exhibited a partial remission ofmean clinical severity, which is a characteristic of the SJL model. Themarkedly lower clinical scores in animals treated twice daily with 100mg/kg R921302 remained significant (p<0.05) throughout the experimentuntil the animals were sacrificed on Day 30. These lower scoresthroughout the treatment period are reflected in the significantly lowercumulative disease index (CDI) and increase in cumulative weight index(CWI) as seen in Table 9. In the group treated with vehicle only, 2/5 ofthe mice relapsed. In the 100 mg/kg/day group, 3/8 of the mice relapsed.None of the mice in the 100 mg/kg twice daily group relapsed.

TABLE 9 SJL female mice treated with Rigel compound R921302 starting onday of immunization with 150 μg PLP 139-151/200 μg MTB (CFA) IncidenceOnset Peak Mortality CDI CWI Placebo 10/10 11.8 ± 0.5 5.1 ± 0.3 1/10^(a)53.2 ± 7.1 118.1 ± 6.4 Control 100 mg/kg 10/10 12.3 ± 0.7 4.3 ± 1.3 0/1044.1 ± 14.5 124.4 ± 6.0 1x/day 100 mg/kg 10/10 13.0 ± 1.2^(b) 4.3 ± 1.43/10^(a) 33.7 ± 11.4^(b) 133.5 ± 6.8^(b) 2x/day CDI = Cumulative DiseaseIndex to day +26 CWI = Cumulative Weight Index to day +23 ^(a)=Mortality due to non-EAE, feeding related injuries or sacrificedhydrocephalic animals. ^(b)= Significant difference between Control vs.Experimental groups (p < 0.05) determined via Students two-tailed ttest.

SJL mice treated with R921302 at disease onset (Day 11) at a dose levelof 200 mg/kg twice daily showed a significant decrease (p=0.003) in CDI(53.5±16.9 in animals treated with R921302 compared with 72.9 ±8.9 inthe animals treated with vehicle alone). Further, there was a dramaticdecrease in the number of relapses in animals treated with R921302(2/12) compared with the number of relapses in animals treated withvehicle (7/11). Results are summarized in Table 10 and FIG. 16.

TABLE 10 SJL female mice treated with Rigel compound R921302 starting onday of onset Mean score at Incidence treatment Peak Mortality RelapsesCDI Control 11/11 3.9 ± 1.6 5.0 ± 0.4 0/11 7/11 72.9 ± 8.9  200 mg/kg12/12 3.4 ± 1.6 4.3 ± 0.7 1/12 2/12 53.5 ± 16.9 2x/day P value 1.00 0.480.02 0.97 0.055 0.003 CDI = Cumulative Disease Index to day +27

7.18.5 The 2,4-Pyrimidinediamine Compounds of the Invention InhibitT-Cell Activation 7.18.5.1 Description

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit activation of T-Cells was shown using a variety of assaysutilizing a Jurkat T-cell cell line and Primary T-cell cultures.Inhibition of activation of Jurkat T-cells in response to T-cellreceptor (TCR) stimulation was measured by quantifying the upregulationof the cell surface marker CD69. Inhibition of primary T-cell activationwas measured by quantifying the release of cytokines, including tumornecrosis factor alpha (TNF), interleukin 2 (IL-2), interleukin 4 (IL-4)interferon gamma (IFNg) and granulocyte macrophage colony stimulatingfactor (GMSCF), in response to TCR/CD28 co-stimulation.

7.18.5.2 Screening for Inhibition of Jurkat T-Cell Activation

Human Jurkat T-cells (clone N) were routinely cultured in RPMI 1640medium (Mediatech) supplemented with 10% fetal calf serum (FBS)(Hyclone), penicillin and streptamycin. The screening process took placeover three days.

On the first day of the screen, cultured cells were spun down on acentrifuge (1000 rpm, 5 minutes) and resuspended at 3.0×10⁵ cells/ml inRPMI+5% FBS. On the second day of the screen, cells were spun down at1000 rpm for 5 minutes and resuspended in RPMI+5% FBS at 1.3×10⁵cells/ml. 85 μl of this cell suspension were added to the wells ofU-bottom 96 well plates (Corning) 85 μl of compound or diluted RPMI+5%FBS (as a control) only was added to each well and incubated at 37° C.for 1 hour. The cells were then stimulated with anti-TCR (C305) at: 500ng/ml by adding a 8× solution in 25 μl to the plated cells. The cellswere then incubated at 37° C. for 20 hrs.

On the third day of the screen, the plates were spun at 2500 RPM for 1minute on a Beckman GS-6R centrifuge, and the medium was then removed.50 μl staining solution (1:100 dilution of anti-CD69-APC antibody(Becton Dickenson) in PBS+2% FBS) was then added to each well, followedby incubation of the plates 4 degrees for 20 minutes in the dark. 150 μlof wash buffer (PBS+2% FBS) was then added to each well, and the plateswere spun at 3000 RPM for 1 minute. The supernatant was again removed,and the pellet was resuspended by vortexing gently. 75 μl of PBS+2% FBS+Cytofix (1:4 dilution) was then added, the plates gently vortexed andwrap in aluminum foil. Cells from the plates were read using a flowcytometer coupled to an automated liquid handling system.

Varied concentrations of compound were compared to solvent only todetermine the inhibition of T-cell activation IC₅₀ of each compound.Representative TC₅₀s for 2,4-pyrimidinediamine compounds of theinvention are shown in Table 11.

7.18.5.3 Isolation of Primary T-Cells

2E8-4E8 PBMC or proliferating T cells grown in rIL-2 from healthy humandonors were suspended in PBS were spun down (1500 rpm, 8-10 minutes) andresuspended in 100 ml RPMI Complete media (1% Pen-Strep, 1% L-Glutamine,10 mM HEPES). The cells were plated in T175 flasks (37° C., 5% CO₂) andmonocytes were allowed to adhere for 2-3 hours. After monocyteattachment, non-adherent cells were harvested, counted by hemocytometer,washed several times with PBS then resuspended in Yssels Complete Media(Modified IMDM Media with 1% Human AB Serum, 1% Pen-Strep, 1%L-Glutamine, 10 mM HEPES) at 1.5 4E6 cells/mL. 90 uL of the celldilution were then added to compounds diluted to 2× in Yssel's media andincubated for 30 minutes at 37° C. (5% CO₂). After this preincubationstep the compound/cell mixture was transferred to stimulation plates, asdescribed below.

7.18.5.4 Screening for Inhibition of Cytokine Production in StimulatedPrimary T-Cell

Stimulation plates were prepared by coating 96 well plates with 5 μg/mlαCD3 (BD PharMingen, Catalog #555336)+10 μg/ml αCD28 (Beckman Coulter,Catalog #IM1376) in PBS (no Ca²⁺/Mg²⁺) at 37° C. (5% CO₂) for at 3-5hours. After incubation with the stimulation antibodies, the cocktailwas removed and the plates washed 3 times with PBS prior to addition ofthe primary T cell/compound mixture.

The compound/cell mixture was transferred to the stimulation plates andincubated for 18 hr at 37° C. (5% CO₂). After the cell stimulation, ˜150μl supernatant were transferred from each well into 96-well filterplates (Coming PVDF Filter Plates) spun down (2000 rpm, 2-3 minutes) andeither used immediately for ELISA or LUMINEX measurements or frozen downat −80° C. for future use.

IL-2 ELISAs were performed using the Quantikine Human IL-2 ELISA kit(R&D Systems, Catalog # D2050) as described by the manufacturer andabsorption was measured on a spectrophotometer at 450 nm wavelength.Blank values were substracted and absorbances were converted to pg/mLbased on the standard curve.

Luminex immunoassay multiplexing for TNF, IL-2, GMSCF, IL-4 and IFNg wasperformed essentially as described by the manufacturer (UpstateBiotechnology). Essentially 50 uL of sample was diluted into 50 uL assaydiluent and 50 uL incubation buffer, then incubated with 100 uL of thediluted detection antibody for 1 hr at RT in the dark. The filter platewas washed 2× in Wash Buffer, then incubated with 100 uL of the dilutedsecondary reagent (SAV-RPE) for 30 min at RT in the dark. Finally theplates were washed 3 times and bead identification and RPE fluorescentmeasured by the Luminex instrument.

Varied concentrations of compound were compared to solvent only todetermine the inhibition of T-cell activation IC₅₀ of each compound.Representative IC₅₀s for 2,4-pyrimidinediamine compounds of theinvention are shown in Table 11.

7.18.6 The 2,4-Pyrimidinediamine Compounds of the Invention InhibitB-Cell Activation 7.18.6.1 Description

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit activation of B-cells was shown using primary B-cells in a cellsurface marker assay using a fluorescence activated cell sorter (FACS).Inhibition of activation of primary B-cells in response to B-cellreceptor (BCR) stimulation was measured by quantifying the upregulationof the cell surface marker CD69.

7.18.6.2 Isolation of Primary B-Cells

Primary human B-cells were isolated from buffy coat, the white celllayer that forms between the red cells and the platelets whenanti-coagulated blood is centrifuged, or from fresh blood usingCD19-Dynal® beads and a FACS. Buffy coat was obtained from the StanfordMedical School Blood Centre, prepared on the same day by the blood bank,stored and transported cold (with ice). The buffy coat (approx 35 mL)was placed in a 500 mL conical sterile centrifuge pot and cooled on ice,then diluted with cold PBS containing 0.2% BSA (Sigma: A7638) and sodiumcitrate (0.1%, Sigma: S-5570) (P—B—C) to a total volume of 200 mL andmixed gently. Fresh blood was collected from donors in 10 mL vacutainerscontaining heparin (1 vacutainer collects approximately 8.5 mL blood).The blood was cooled on ice, transferred into 50 mL falcon tubes (20mL/tube) or a 500 mL conical sterile centrifuge pot, and diluted with anequal volume P—B—C.

25 mL diluted blood or buffy coat was layered onto 15 mL cold ficoll andplaced back on ice. The ficoll layered blood was centrifuged (BeckmanGS-6R) for 45 minutes at 2000 rpm, 4° C. to separate the PeripheralBlood Mononuclear Cells (PBMC) from the Red Blood Cells (RBC) andgranulocytes. The top aqueous layer was then aspirated until 1 inchabove the PBMC layer. The PBMCs were transferred from every 2 ficolltubes into one clean 50 mL falcon tube (=approx 10 mL/tube). Thetransferred PBMCs were diluted 5× with icecold PBS with 0.2% BSA (P—B)and centrifuged for 20 min at 1400 rpm and 4° C. The supernatant (thismay be cloudy) was then aspirated and the PBMCs resuspended into 25 mLP—B and the cells counted (using a 1:5 dilution) and kept on ice.

The cells were then positively selected using anti-CD 19 antibodycoupled to magnetic beads (Dynal®) as per manufacturer's instructions.The approximate required amount of CD19-Dynal® beads (CD19-coated dynabeads M-450 (pabB), Dynal®) was calculated by estimating the number ofB-cells as 5% of PBMCs counted and adding approximately10 beads per cellfrom the bead stock (4×10⁸ beads/mL). The CD19-Dynal® beads were washed2× in P—B in a 5 mL tube using the Dynal® magnet, then added into thesuspended PBMCs. This mixture was then passed through the Dynal® magnetand washed several times to separate the bead-bound cells.

7.18.6.3 Screening Compounds for Inhibition of B-cell Activation

After separation, the beads and antibody were removed using Dynal®CD19-DETACHaBEAD® for 45 min at 30° C. Yield is typically 2×10⁷ B-cellsper buffy coat. B-cells were washed and resuspended as 1E6 cells/mL inRPMI1640+10% FBS+Penicillin/Streptavidin+1 ng/mL IFNα8. Cells wererested overnight at 37° C. and 5% CO₂.

The following day, cells were washed and resuspended in RPMI+2.5% FBS to1×10⁶ cells/mL. Cells were then aliquoted into a V-bottom 96-well plate(Corning) at 65 uL cells per well. By robot, 65 uL of a 2× compound wasadded to the cells with final concentration of DMSO at 0.2%, andincubated for 1 hr at 37° C. Cells were then stimulated with 20 uL 7.5×α-IgM from Jackson laboratories (final 5 ug/mL) for 24 hrs. At day 3,the cells were spun down and stained for CD69 and analyzed by FACS gatedon the live cells (by light scatter).

Varied concentrations of compound were compared to solvent only todetermine the inhibition of B-cell activation IC₅₀ of each compound.Representative IC₅₀s for 2,4-pyrimidinediamine compounds of theinvention are shown in Table 11.

7.18.7 The 2,4-Pyrimidinediamine Compounds of the Invention InhibitMacrophage Activation

7.18.7.1 Description

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit activation of differentiated macrophages was shown by measuringthe release of cytokines from stimulated macrophages. Release of tumornecrosis factor alpha (TNF) and interleukin 6 (IL-6) was quantified inresponse to IgG or LPS stimulation.

7.18.7.2 Purification and Culture of Human Macrophages

CD 14+ monocytes were purified from from PBMC (Allcells # PB002) usingthe Monocyte Isolation kit (Miltenyi biotec #130-045-501) as per themanufacturer's instructions. Purity was assessed by measuring thepercentage of CD14+ cells by flow cytometry. Typically >90% purity isachieved. The purified CD14+ cells are then plated out (6×10⁶ cells/150cm TC dish in 15 mls media) in Macrophage-SFM (Gibco #12065-074) with100 ng/ml of M-CSF (Pepro Tech #300-25) and allowed to differentiate forfive days. At the end of that period, cell morphology and cell surfacemarkers (CD14, HLA-DR, B7.1, B7.2, CD64, CD32, and CD16) reflected thepresence of mature differentiated macrophage.

7.18.7.3 Stimulation with IgG

Immulon 4HBX 96 well plates (VWR #62402-959) were coated with pooledhuman IgG (Jackson Immunoresearch lab #009-000-003) at 10 ug/wellovernight at 4° C. or 1 hr at 37° C. A negative control consisting ofthe F(ab′)2 fragment was also coated to assess background stimulation.Unbound antibody was washed away 2× with 200 ul PBS. 20 ul of 5×compound was added to each well, followed by the addition 15 k cells ofdifferentiated macrophage in 80 uL that had been scraped off of theplates. The cells were incubated for 16 hr in a 37° C. incubator, andsupernatants were collected for Luminex analysis for IL-6 and TNFα,essentially as described for the primary T-cells, above.

7.18.7.4 Stimulation with LPS

For stimulation with LPS, 10 uL of a 10× stock solution was added to thepreincubated cell-compound mixture to a final concentration of 10 ng/mL.The cells were then incubated for 16hr at 37° C. and supernatants wereanalyzed as described above.

Varied concentrations of compound were compared to solvent only todetermine the IC₅₀ of each compound for each cytokine RepresentativeIC₅₀ s for 2,4-pyrimidinediamine compounds of the invention are shown inTable 11.

TABLE 11 Monocytes/ Jurkat 1° T-Cell 1° B-Cell Macrophage CD69 IC50 TNFIC50 IL2 IC50 GMSCF IC50 IL4 IC50 IFNg CD69 IC50 TNF IC50 IL-6 IC50Compound (in μM) (in μM) (in μM) (in μM) (in μM) IC50 (in μM) (in μM)(in μM) (in μM) R070790 9999 R908696 9999 R908697 9999 R908698 3.748R908699 1.033 R908700 13.724 R908701 0.302 R908702 0.37 R908703 1.399R908704 3.037 R908705 5.876 R908706 0.405 R908707 9.372 R908709 3.394R908710 4.277 R908711 4.564 R908712 0.348 R908734 3.555 R908953 1.982R909236 9999 R909237 9999 R909238 5.021 R909239 3.063 R909240 2.845R909241 3.52 R909242 3.8 R909243 2.245 R921219 0.441 0.546 0.131 R9092450.78 R909246 2.166 R909247 3 R909248 33.258 R909249 9999 R909250 9999R909251 0.664 R909252 0.655 R909253 3.082 R909255 1.973 R909259 9999R909260 3.329 R909261 2.935 R909263 6.195 R909264 3.241 R909265 11.988R909266 12.983 R909267 9999 R909268 0.997 R909290 1.562 R909292 3.315R909317 0.224 0.595 1.324 1.743 0.876 1.573 R909322 3.028 1.259 0.839R920395 0.726 R920410 1.981 2.989 3.36 3.2 0.546 4.307 0.706 R9206649999 R920665 10.883 R920666 9999 R920668 9999 R920669 19.813 R92067014.322 R920671 9999 R920672 9999 R920818 9999 R920819 9999 R920820 9999R920846 10.404 R920860 9999 R920861 3.28 R920893 1.4 R920894 2.024R920910 2.38 R920917 2.649 R925734 9999 R925745 9999 R925746 9999R925747 9999 R925755 1.906 R925757 9999 R925758 18.209 R925760 20.246R925765 9999 R925766 9999 R925767 9999 R925768 9999 R925769 9999 R9257709999 R925771 7.187 R925772 9999 R925773 14.414 R925774 7.498 R9257759999 R925776 17.059 R925778 3.398 R925779 9999 R925783 9999 R925784 9999R925785 3.117 R925786 9999 R925787 9999 R925788 16.898 R925790 16.992R925791 9999 R925792 8.65 R925794 9999 R925795 9999 R925796 1.827R925797 1.511 R925798 9999 R925799 9999 R925800 9999 R925801 9999R925802 9999 R925803 9999 R925804 9999 R925805 9999 R925806 9999 R9258079999 R925808 9999 R925810 21.332 R925811 9999 R925812 9999 R92581414.163 R925815 9999 R925816 4.664 R925819 9999 R925820 9999 R925821 9999R925822 9999 R925823 9.326 R925838 9999 R925842 9999 R925845 6.968R925846 9999 R925849 8.022 R925852 9999 R925853 9999 R925855 9999R925856 9999 R925857 9999 R925858 9999 R925860 41.865 R925861 20.195R925862 9999 R925863 2.962 R925864 19.127 R925865 9999 R926016 9999R926017 20.775 R926018 9999 R926037 9999 R926038 9999 R926039 9999R926058 9999 R926064 9999 R926065 6.731 R926068 11.416 R926069 4.307R926072 9999 R926086 6.635 R926108 10.373 R926109 16.117 R926110 3.474R921218 3.935 3.24 1.081 R926113 4.379 R926114 9.913 R926145 17.689R926146 9999 R926147 9999 R926206 9999 R926209 9999 R926210 4.379R926211 14.957 R926212 0.56 R926213 8.864 44 R926218 9999 R926220 9999R926221 9999 R926222 9999 R926223 9999 R926224 9999 R926225 9999 R9262289999 R926229 9999 R926230 9999 R926234 9999 R926237 9999 R926238 9999R926240 9999 R926241 13.768 R926242 3.824 R926243 2.986 R926245 11.086R926248 1.537 R926249 0.954 R926252 9999 R926253 9999 R926254 9999R926255 9999 R926256 9999 R926257 9999 R926258 9999 R926259 12.96R926319 15.584 R926320 9999 R926321 1.293 R926325 9999 R926331 9999R926339 2.149 R926340 9999 R926341 3.676 R926376 9999 R926386 9999R926387 3.852 R926394 9999 R926395 17.741 R926396 6.594 R926397 12.469R926398 9999 R926399 9999 R926400 9999 R926401 9999 R926402 9999 R9264039999 R926404 9999 R926405 7.617 R926408 9999 R926409 3.539 R92641116.926 R926412 2.383 R926461 3.388 R926467 9999 R926469 9999 R92647410.775 R926475 9999 R926476 3.904 R926477 9999 R926479 9999 R926480 9999R926481 9999 R926482 8.261 R926483 9999 R926484 9999 R926485 9999R926486 1.745 R926487 48.937 R926488 2.429 R926489 9999 R926491 2.727R926492 3.335 R926493 3.524 R926494 12.507 R926495 11.904 0.643 R9264964.387 R926497 3.267 R926498 5.732 R926499 0.56 R926500 2.367 R9265011.681 R926502 1.626 R926503 2.599 R926504 1.784 R926505 1.145 R9265062.676 R926508 1.006 0.917 0.948 R926509 1.078 R926510 0.122 R9265111.729 R926514 15.6 R926516 17.782 R926526 9999 R926527 21.197 R9265289999 R926535 9999 R926536 9999 R926555 9999 R926559 11.248 R926560 9999R926561 9999 R926562 1.246 R926563 9999 R926564 9999 R926565 9999R926566 9999 R926567 9999 R926569 9999 R926571 9999 R926572 9999 R9265749999 R926576 9999 R926585 9999 R926586 9999 R926587 9999 R926588 9999R926589 9999 R926591 9999 R926593 1.282 R926594 1.252 R926595 9999R926604 9999 R926605 9999 R926614 6.537 R926615 1.871 R926616 1.912R926617 9999 R926620 9999 R926623 10.015 R926662 9999 R926675 2.369R926676 9999 R926680 5.703 R926681 2.002 R926682 5.946 R926683 7.635R926688 3.779 R926690 13.398 R926696 7.645 R926698 9999 R926699 1.861R926700 0.51 R926701 9999 R926702 18.583 R926703 7.873 R926704 9.271R926705 2.651 R926706 9999 R926707 2.683 R926708 3.299 R926709 2.47R926710 4.273 R926711 3.788 R926712 6.351 R926713 8.219 R926714 5.632R926715 2.357 R926716 3.618 R926717 3.75 R926718 12.441 R926719 9999R926720 9999 R926721 3.461 R926722 9999 R926723 9999 R926724 9999R926725 3.368 R926726 9999 R926727 9999 R926728 9999 R926730 1.84R926731 9999 R926732 5.256 R926733 3.594 R926734 11.276 R926735 5.982R926736 14.12 R926737 2.384 R926738 2.216 R926739 2.093 R926740 9999R926741 4.593 R926742 0.717 R926743 9999 R926744 9999 R926745 1.4841.498 R926746 3.696 R926747 3.278 R926748 2.769 R926749 4.684 R9267500.535 R926751 5.592 R926752 1.734 R926753 0.393 R926754 13.245 R9267557.364 R926756 3.774 R926757 2.737 R926759 1.71 R926760 10.25 R9267610.694 R926762 0.703 R926763 3.717 R926764 2.165 R926765 8.003 R9267664.24 R926767 2.667 R926768 0.973 R926769 2.79 R926770 0.891 R9267713.473 R926772 2.043 R926773 1.844 R926774 12.741 R926775 9999 R92677612.475 R926777 9999 R926778 9999 R926779 9999 R926780 2.158 R9267819.811 R926782 1.221 R926783 2.95 R926784 2.379 R926785 2.583 R9267867.361 R926787 9999 R926788 9999 R926789 9999 R926790 9999 R926791 1.751R926792 9.975 R926795 9999 R926796 4.205 R926797 9999 R926798 9999R926799 9999 R926800 9999 R926801 9999 R926802 5.909 R926803 9999R926804 9999 R926805 9999 R926806 6.076 R926807 10.136 R926808 1.76R926809 9999 R926810 5.069 R926811 1.284 R926812 6.76 R926813 5.101R926814 9999 R926815 9999 R926816 0.739 R926826 3.732 R926827 2.135R926828 1.006 R926829 3.095 R926830 4.161 R926831 1.271 R926832 2.988R926833 11.797 R926834 2.568 R926835 3.585 R926836 14.528 R926837 9999R926838 10.684 R926839 2.485 R926840 12.234 R926841 3.279 R926842 9999R926843 9999 R926844 9999 R926845 9999 R926846 9999 R926847 11.782R926848 1.72 R926851 3.089 R926852 9999 R926853 9999 R926854 48.759R926855 9999 R926856 9999 R926857 9999 R926858 9999 R926859 9999 R9268609999 R926861 9999 R926862 7.746 R926863 9999 R926866 9999 R926869 9999R926873 9999 R926875 9999 R926876 9999 R926877 9999 R926878 9999 R9268792.554 R926880 6.239 R926881 11.025 R926882 9.049 R926883 9999 R9268849999 R926885 9999 R926886 1.136 R926887 5.92 R926888 5.582 R926889 9999R926890 11.291 R926891 1.548 0.803 1.135 0.942 R926892 1.635 R9268939999 R926894 9999 R926895 9999 R926896 9999 R926897 9999 R926898 9999R926899 9999 R926900 9999 R926902 9999 R926903 9999 R926904 1.363R926905 6.488 R926906 9999 R926907 17.14 R926908 30.57 R926909 4.65R926910 9999 R926911 9999 R926912 9999 R926913 5.652 R926914 9999R926915 9999 R926917 4.741 R926918 4.689 R926919 9999 R926920 9999R926921 9999 R926922 6.123 R926923 7.203 R926924 3.228 R926925 5.868R926926 13.105 R926927 5.527 R926928 9999 R926929 3.998 R926930 10.481R926931 2.933 R926932 2.907 R926933 2.79 R926934 6.011 R926935 11.794R926936 7.883 R926937 9999 R926938 9999 R926939 9999 R926940 9999R926941 9999 R926942 9999 R926943 18.527 R926944 3.43 R926945 4.243R926946 9.4 R926947 13.298 R926956 0.749 R926968 2.024 R926976 1.164.369 7.618 R926982 0.394 R927016 7.156 R927017 8.157 R927018 17.68R927019 9999 R927050 0.112 0.6 0.928 1.118 0.275 0.916 0.438 0.108 0.066R927064 2.735 9999 9999 9999 1.754 R927069 0.93 8.505 5.65 R935000 9999R935001 9999 R935002 9999 R935003 9999 R935004 9999 R935005 9999 R9350069999 R935016 5.363 R935019 9999 R935020 9999 R935021 9999 R935023 9999R935025 7.949 R935075 5.366 R935076 9999 R935077 9999 R935114 9999R935117 9999 R935134 9999 36.11 R935135 9999 R935136 9999 R935137 24.124R935138 0.46 R935139 10.963 R935140 2.158 R935141 9999 R935142 9.665R935143 3.843 R935144 9999 13.31 R935145 5.339 R935146 9999 R9351471.981 R935148 9999 R935149 9999 R935150 20.372 R935151 1.961 R93515219.866 R935153 7.071 R935154 1.646 R935155 9999 R935156 1.845 R9351579999 R935158 2.47 R935159 9999 R935160 2.37 R935161 3.134 R935162 3.377R935163 9999 R935164 3.319 R935165 9999 R935166 9999 R935167 9999R935168 3.71 R935169 7.539 R935170 6.027 R935171 3.927 R935172 9999R935173 3.908 R935174 3.99 R935175 1.743 R935176 1.981 R935177 4.154R935178 3.04 R935179 2.999 R935180 3.571 R935181 8.983 R935182 23.856R935183 2.271 R935184 4.082 R935185 4.107 R935186 1.095 R935187 9999R935188 1.803 R935189 0.736 R935190 3.472 R935191 2.938 R935192 5.39R935193 1.596 R935194 0.732 R935196 1.103 R935197 2.428 R935198 1.453R935199 2.509 R935202 1.941 R935203 9999 R935204 3.869 R935205 10.715R935206 9999 R935207 9999 R935208 2.877 R935209 9999 R935211 7.06R935212 4.682 R935213 3.089 R935214 1.378 R935215 7.955 R935216 3.475R935217 9999 R935218 22.692 R935219 5.567 R935220 8.067 R935221 9999R935222 3.535 R935223 4.574 R935224 9999 R935225 7.422 R935237 9999R935238 6.727 R935239 1.726 R935240 2.709 R935242 9999 R935248 1.898R935249 4.833 R935250 6.236 R935255 0.668 R935256 0.92 R935258 6.26R935259 3.458 R935261 2.181 R935262 3.113 R935263 2.017 R935264 1.408R935266 9999 R935267 3.93 R935268 2.906 R935269 7.578 R935271 0.858R935279 1.984 R935286 2.497 R935287 1.697 R935288 9999 R935289 5.338R935290 3.43 R935291 3.139 R935292 3.61 R935293 1.337 R935294 8.16R935295 14.241 R935296 9999 R935297 5.701 R935298 2.317 R935299 0.824R935300 3.384 R935301 2.317 R935302 0.8 R935303 0.653 R935304 0.497R935305 1.834 R935306 4.726 R935307 1.407 R935308 1.265 R935309 0.779R935310 0.88 R935320 9999 R935321 9999 R935322 9999 R935323 9999 R9353249999 R935336 2.878 R935337 2.537 R935338 5.891 R935339 9999 R935340 9999R935366 4.182 R935368 9999 R935372 30.713 R935391 6.041 0.669 1.1570.959 R935393 9999 R940079 9999 R940089 9999 R940090 9999 R940095 9999R940100 9999 R940110 9999 R940215 9999 R940216 1.283 R940217 9999R940222 9.471 R940233 2.171 R940253 17.367 R940254 3.763 R940255 1.509R940256 4.745 R940257 9999 R940258 9999 R940260 9999 R940261 10.948R940262 6.448 R940263 10.05 R940264 9999 R940265 5.563 R940266 9999R940267 9999 R940269 1.895 R940270 9999 R940271 9999 R940275 16.37R940276 2.532 R940277 1.223 R940280 9999 R940281 9999 R940282 6.709R940283 9999 R940284 78.15 R940285 9999 R940286 4.4 R940287 6.197R940288 3.485 R940289 3.646 R940290 1.16 R940291 9.446 R940292 2.781R940293 9999 R940294 9999 R940296 1.23 R940297 9999 R940299 24.942R940300 9.284 R940301 1.314 R940304 9999 R940306 11.036 R940307 2.063R940309 9999 R940311 4.123 R940312 16.178 R940314 7.032 R940316 4.278R940317 3.282 R940318 1.387 R940320 7.818 R940321 3.68 R940322 4.57R940323 0.557 0.11 R940336 9999 R940337 1.821 R940338 0.708 R9403425.124 R921303 0.423 0.796 1.02 1.178 0.366 1.28 0.217 R940344 7.735R940345 5.395 R940346 2.086 R940347 0.581 0.0992 1.894 1.613 0.212 1.6730.47 0.038 0.019 R940350 0.308 1.513 2.993 2.45 0.501 2.471 0.297R940352 3.53 0.876 R940353 20.699 R940358 0.159 R940361 0.39 R9403630.141 0.242 0.133 0.095 R940366 0.086 0.086 0.097 R945025 7.033 R94503215.179 R945033 9999 R945034 9999 R945035 9999 R945036 9999 R945037 9999R945038 9999 R945040 9999 R945041 9999 R945042 9999 R945043 9999 R9450457.602 R945046 4.078 R945047 3.206 R945048 2.231 R945051 9999 R9450529999 R945053 2.674 R945056 9999 R945057 9999 R945060 6.076 R945061 9999R945062 9999 R945063 6.038 R945064 4.684 R945065 14.427 R945066 43.243R945067 9999 R945068 9999 R945070 9999 R945071 0.631 R945096 2.802R945097 9999 R945109 9.637 R945110 9999 R945117 9999 R945118 9.492R945124 6.161 R945125 9999 R945126 9999 R945127 11.084 R945128 4.311R945129 6.08 R945130 9999 R945131 19.162 R945132 20.194 R945133 9.14R945135 4.367 R945137 5.429 R945138 9999 R945139 13.869 R945140 2.094R945142 1.88 R945144 1.656 R945145 9999 R945146 9999 R945147 9999R945148 16.217 R945149 1.226 R945150 1.112 R945151 9999 R945152 9999R945153 9.738 R945155 7.067 R945156 2.29 R945157 1.477 R945162 9999R945163 9999 R945164 9999 R945165 9999 R945166 9999 R945167 5.072R945168 9999 R945169 2.38 R945170 4.123 R945171 3.194 R945172 3.132R945173 2.884 R945175 3.787 R945236 2.921 R945237 0.838 R945242 1.707R945263 4.467 R921304 0.141 1.497 2.772 1.567 0.366 2.894 0.167 R9452989.467 R945299 1.063 R950083 9999 R950090 9999 R921302 3.513 1.628 5.1853.207 0.245 3.896 1.17 R950092 9999 R950093 11.28 R950100 5.67 R9501075.424 R950108 9999 R950109 12.782 R950120 12.062 R950121 6.265 R95012213.894 R950123 9999 R950125 9999 R950129 6.88 R950130 9999 R950131 9999R950132 4.638 R950133 4.701 R950134 6.455 R950135 9999 R950137 5.904R950138 9999 R950139 5.454 R950140 22.366 R950141 2.376 R950142 29.078R950143 4.569 R950144 9999 R950145 6.13 R950146 9999 R950147 14.803R950148 9999 R950149 9999 R950150 9999 R950151 14.221 R950152 2.654R950153 9999 R950154 9999 R950155 9999 R950156 9999 R950157 9999 R95015821.381 R950159 8.446 R950160 9999 R950162 8.918 R950163 24.106 R95016418.213 R950165 7.594 R950166 9999 R950167 9999 R950168 10.692 R9501699999 R950170 9999 R950171 4.358 R950172 23.117 R950173 9.184 R9501749999 R950175 9999 R950176 9999 R950177 9999 R950178 22.59 R950179 29.867R950180 2.869 R950181 2.689 R950182 9999 R950183 9999 R950184 9999R950185 9999 R950186 5.944 R950187 22.312 R950188 17.862 R950189 21.963R950190 7.17 R950191 2.586 R950192 1.732 R950193 2.826 R950194 5.131R950195 1.804 R950196 2.081 R950197 2.582 R950198 1.99 R950199 3.214R950200 2.264 R950201 4.502 R950202 9999 R950203 9999 R950204 9999R950205 24.548 R950206 9999 R950207 1.085 R950208 1.766 R950209 3.796R950210 9999 R950211 9999 R950212 9.497 R950213 9999 R950214 9999R950215 5.006 R950216 3.856 R950217 2.795 R950218 3.425 R950219 2.11R950220 2.678 R950221 20.345 R950222 2.008 R950223 2.775 R950224 2.423R950225 2.325 R950226 2.917 R950227 7.112 R950229 3.773 R950230 8.235R950231 8.688 R950232 9.161 R950233 5.305 R950234 9999 R950235 6.262R950236 9.693 R950237 12.901 R950238 9999 R950239 9999 R950240 8.925R950241 5.185 R950244 9999 R950245 9999 R950246 9999 R950247 9999R950251 9999 R950253 10.547 R950254 2.35 R950255 9999 R950261 17.375R950262 3.148 R950263 1.911 R950264 1.988 R950265 0.982 R950266 3.66R950267 1.985 R950290 9999 R950291 9999 R950292 9999 R950293 9999R950294 9.793 R950295 4.713 R950296 1.947 R950344 9999 R950345 6.09R950346 1.948 R950347 2.704 R950348 0.224 R950349 0.363 R950356 5.731R950368 0.125 R950371 1.105 R950372 2.192 R950373 3.614 R950374 1.65R950376 18.08 R950377 5.962 R950378 9999 R950379 0.878 R950380 8.688R950381 0.805 R950382 1.547 R950383 1.026 R950385 2.58 R950386 11.354

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

All literature and patent references cited throughout the applicationare incorporated by reference into the application for all purposes.

1. A compound for formula (1a)

or a salt thereof wherein R⁵ is selected from the group consisting of halo, —F, —CN, —NO₂, —C(O)R^(a), —C(O)OR^(a), —C(O)CF₃, —C(O)OCF₃, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, —OCF₃ and —CF₃ R⁶ is hydrogen or halogen; R⁸ is selected from the group consisting of R^(a), R^(b), R^(a) substituted with one or more of the same or different R^(a) or R^(b), —OR^(a) substituted with one or more of the same or different R^(a) or R^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b), —(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b), —O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b), —C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b), —O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b), —NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂, —NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and —NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b); each R^(a) is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each R^(b) is a suitable group independently selected from the group consisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d), ═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d), —C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c), —C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d), —OC(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c), —[NHC(O)]_(n)R^(d), —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d), —[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c), —[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c); each R^(c) is independently R^(a), or, alternatively, each R^(c) is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R^(a) or suitable R^(b) groups; each R^(d) is independently a protecting group or R^(a); each m is independently an integer from 1 to 3; and each n is independently an integer from 0 to 3; R² is phenyl optionally substituted with one or more of the same or different R⁸ groups; and R⁴ is selected from the group consisting of

wherein each Y¹ is independently selected from the group consisting of O, S, SO, SO₂, SONR³⁶, and NH, and R³⁶ is hydrogen or alkyl.
 2. The compound of claim 1 wherein R⁸ is R^(a) or R^(a) substituted with one or more of the same or different R^(a) or R^(b).
 3. The compound of claim 2 wherein R⁸ is morpholinyl or piperazinyl optionally substituted with one or more of the same or different R^(a) or R^(b).
 4. The compound according to claim 1, wherein R² is mono substituted with an R⁸ group.
 5. The compound according to claim 2, wherein the R⁸ group is at the para position.
 6. The compound according to claim 1 wherein NR^(c)R^(c) is a 5-6 membered saturated cycloheteroalkyl ring which optionally includes one or more of the same or different heteroatoms.
 7. The compound according to claim 6 wherein the cycloheteroalkyl is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.
 8. The compound according to claim 1 wherein R⁵ is fluoro and R⁶ is H.
 9. The compound according to claim 8, wherein R⁸ is independently selected from the group consisting of R^(d), —NR^(c)R^(c), —(CH₂)_(m)—NR^(c)R^(c), —C(O)NR^(c)R^(c), —(CH₂)_(m)—C(O)NR^(c)R^(c), —C(O)OR^(d), —(CH₂)_(m)—C(O)OR^(d) and —(CH₂)_(m)—OR^(d).
 10. The compound according to claim 8, wherein R⁴ is

wherein R² is phenyl substituted with one or more R⁸.
 11. A compound according of formula

wherein: R^(x) and R³′ independently are either both H or both methyl; and R^(z) is (a) piperizin-1-yl substituted on the N at the 4 position with methoxycarbonyl, methylcarbonyl, or methyl, or (b) morpholinyl.
 12. A compound that is 5-Fluoro-N2-(4-morpholinophenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine; N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl]-5-fluoro-N2-[4-(4-methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine; N2-[4-(4-Acetylpiperazino)phenyl]-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine; 5-Fluoro-N2-[4-(4-methylpiperazino)phenyl]-N4-(2H-3-oxo-4H-5-pyrid [1,4]oxazin-6-yl)-2,4-pyrimidinediamine; N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine; or a pharmaceutically acceptable salt of one of the foregoing.
 13. A compound that is N4-(2,2-Dimethyl-2H-3-oxo-4H-5-pyrid [1,4]oxazin-6-yl) -5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine; or a pharmaceutically acceptable salt thereof.
 14. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent. 